Technical Field
[0001] The present invention relates to a system for energy delivery into a patient.
Background
[0002] Energy delivery from a distance involves transmission of energy waves to affect a
target at a distance. It allows for more efficient delivery of energy to targets and
a greater cost efficiency and technologic flexibility on the generating side. For
example, cellular phones receive targets from towers close to the user and the towers
communicate with one another over a long range; this way, the cell phones can be low
powered and communicate over a relatively small range yet the network can quickly
communicate across the world. Similarly, electricity distribution from large generation
stations to the users is more efficient than the users themselves looking for solutions.
[0003] In terms of treating a patient, delivering energy over a distance affords great advantages
as far as targeting accuracy, technologic flexibility, and importantly, limited invasiveness
into the patient. In a simple form, laparoscopic surgery has replaced much of the
previous open surgical procedures and lead to creation of new procedures and devices
as well as a more efficient procedural flow for disease treatment. Laparoscopic tools
deliver the surgeon's energy to the tissues of the patient from a distance and results
in improved imaging of the region being treated as well as the ability for many surgeons
to visualize the region at the same time.
[0004] Perhaps the most important aspect is the fact that patients have much less pain,
fewer complications, and the overall costs of the procedures are lower. Visualization
is improved as is the ability to perform tasks relative to the visualization.
[0005] Continued advances in computing, miniaturization and economization of energy delivery
technologies, and improved imaging will lead to still greater opportunities to apply
energy from a distance into the patient and treat disease.
Summary
[0006] The present invention provides a system for energy delivery into a patient as defined
in claim 1.
[0007] Optional features are specified in the dependent claims.
[0008] In some embodiments, procedures and devices are provided, which advance the art of
medical procedures involving transmitted energy to treat disease. The procedures and
devices follow along the lines of: 1) transmitting energy to produce an effect in
a patient from a distance; 2) allowing for improved imaging or targeting at the site
of treatment; 3) creating efficiencies through utilization of larger and more powerful
devices from a position of distance from or within the patient as opposed to attempting
to be directly in contact with the target as a surgeon, interventional cardiologist
or radiologist might do. In many cases, advanced visualization and localization tools
are utilized as well.
[0009] In some embodiments, a method of treatment includes placing an energy source outside
a patient, operating the energy source so that an energy delivery path of the energy
source is aimed towards a nerve inside the patient, wherein the nerve is a part of
an autonomic nervous system, and using the energy source to deliver treatment energy
from outside the patient to the nerve located inside the patient to treat the nerve.
[0010] In some embodiments, the treatment energy comprises focused energy.
[0011] In some embodiments, the treatment energy comprises non-focused energy.
[0012] In some embodiments, the treatment energy comprises HIFU energy.
[0013] In some embodiments, the treatment energy comprises LIFU energy.
[0014] In some embodiments, the treatment energy is delivered to the nerve to achieve partial
ablation of the nerve.
[0015] In some embodiments, the treatment energy is delivered to the nerve to achieve complete
ablation of the nerve.
[0016] In some embodiments, the treatment energy is delivered to achieve paralysis of the
nerve.
[0017] In some embodiments, the nerve leads to a kidney.
[0018] In some embodiments, the nerve comprises a renal nerve.
[0019] In some embodiments, the nerve comprises a sympathetic nerve connected to the kidney.
[0020] In some embodiments, the nerve comprises an afferent nerve connected to the kidney.
[0021] In some embodiments, the nerve comprises a renal sympathetic nerve at a renal pedicle.
[0022] In some embodiments, the nerve comprises a nerve trunk adjacent to a vertebra.
[0023] In some embodiments, the nerve comprises a ganglion adjacent to a vertebra.
[0024] In some embodiments, the nerve comprises a dorsal root nerve.
[0025] In some embodiments, the nerve leads to an adrenal gland.
[0026] In some embodiments, the nerve comprises a motor nerve.
[0027] In some embodiments, the nerve is next to a kidney.
[0028] In some embodiments, the nerve is behind an eye.
[0029] In some embodiments, the nerve comprises a celiac plexus.
[0030] In some embodiments, the nerve is within or around a vertebral column.
[0031] In some embodiments, the nerve extends to a facet joint
[0032] In some embodiments, the nerve comprises a celiac ganglion.
[0033] In some embodiments, the act of operating the energy source comprises positioning
the energy source.
[0034] In some embodiments, the energy source comprises an ultrasound energy source.
[0035] In some embodiments, the ultrasound energy source is used to deliver the treatment
energy to the nerve from multiple directions outside the patient.
[0036] In some embodiments, the treatment energy is delivered to modulate the nerve without
damaging the nerve.
[0037] In some embodiments, the method further includes determining a position of a renal
vessel using an imaging device located outside the patient.
[0038] In some embodiments, the position of the renal vessel is used to determine a position
of the nerve.
[0039] In some embodiments, the imaging device comprises a CT device, an MRI device, a thermography
device, an infrared imaging device, an optical coherence tomography device, a photoacoustic
imaging device, a PET imaging device, a SPECT imaging device, or an ultrasound device.
[0040] In some embodiments, the method further includes determining a position of the nerve
inside the patient.
[0041] In some embodiments, the act of determining the position of the nerve inside the
patient comprises determining a position of a renal vessel to target the nerve that
surrounds the renal vessel.
[0042] In some embodiments, the renal vessel comprises a renal artery.
[0043] In some embodiments, the act of determining the position of the nerve inside the
patient comprises using a Doppler triangulation technique.
[0044] In some embodiments, the imaging device comprises a MRI device.
[0045] In some embodiments, the imaging device comprises a CT device.
[0046] In some embodiments, the treatment energy comprises HIFU energy, and the imaging
device comprises a MRI device.
[0047] In some embodiments, the treatment energy comprises HIFU energy, and the imaging
device comprises an ultrasound device.
[0048] In some embodiments, the nerve leads to a kidney, and the imaging device comprises
a MRI device.
[0049] In some embodiments, the nerve leads to a kidney, and the imaging device comprises
an ultrasound device.
[0050] In some embodiments, the nerve leads to a kidney, and the imaging device is used
to obtain a doppler signal.
[0051] In some embodiments, the treatment energy is delivered to a kidney to decrease a
sympathetic stimulus to the kidney, decrease an afferent signal from the kidney to
an autonomic nervous system, or both.
[0052] In some embodiments, the method further includes delivering testing energy to the
patient to determine if there is a reaction resulted therefrom, wherein the testing
energy is delivered before the treatment energy is delivered from the energy source.
[0053] In some embodiments, the testing energy comprises heat or vibratory energy, and the
method further comprises performing a test to detect sympathetic nerve activity.
[0054] In some embodiments, the testing energy comprises a stimulus applied to a skin, and
the method further comprises detecting an output from the patient.
[0055] In some embodiments, the output comprises a heart rate.
[0056] In some embodiments, the test energy is delivered to stimulate a baroreceptor complex,
and the method further includes applying pressure to a carotid artery, and determining
whether a blood pressure decreases after application of the pressure to the carotid
artery.
[0057] In some embodiments, the test energy is delivered using an ultrasound device that
is placed outside the patient.
[0058] In some embodiments, the treatment energy from the energy source is delivered if
the blood pressure decreases or if the blood pressure decreases at a rate that is
above a prescribed threshold.
[0059] In some embodiments, the treatment energy is delivered to treat hypertension.
[0060] In some embodiments, the treatment energy is delivered to treat glaucoma.
[0061] In some embodiments, the energy source is operated so that the energy source aims
at a direction that aligns with a vessel that is next to the nerve.
[0062] In some embodiments, the method further includes tracking a movement of a treatment
region containing the nerve.
[0063] In some embodiments, the energy delivery path of the energy source is aimed towards
the nerve by using a position of a blood vessel that is surrounded by the nerve.
[0064] In some embodiments, the method further includes delivering a device inside the patient,
and using the device to determine a position of the nerve inside the patient, wherein
the energy source is operated based at least in part on the determined position so
that the energy delivery path is aimed towards the nerve.
[0065] In some embodiments, the device is placed inside a vessel that is surrounded by the
nerve, and the position of the nerve is determined indirectly by determining a position
of the vessel.
[0066] In some embodiments, a system for treatment includes an energy source for placement
outside a patient, wherein the energy source is configured to aim an energy delivery
path towards a nerve that is a part of an autonomic nervous system inside the patient,
and wherein the energy source is configured to deliver treatment energy from outside
the patient to the nerve located inside the patient to treat the nerve.
[0067] In some embodiments, the energy source is configured to provide focused energy.
[0068] In some embodiments, the energy source is configured to provide non-focused energy.
[0069] In some embodiments, the energy source is configured to provide HIFU energy.
[0070] In some embodiments, the energy source is configured to provide LIFU energy.
[0071] In some embodiments, the energy source is configured to provide the treatment energy
to achieve partial ablation of the nerve.
[0072] In some embodiments, the energy source is configured to deliver the treatment energy
to achieve complete ablation of the nerve.
[0073] In some embodiments, the energy source is configured to deliver the treatment energy
to achieve paralysis of the nerve.
[0074] In some embodiments, the energy source comprises an ultrasound energy source.
[0075] In some embodiments, the ultrasound energy source is configured to deliver the treatment
energy to the nerve from multiple directions outside the patient while the ultrasound
energy source is stationary relative to the patient.
[0076] In some embodiments, the energy source is configured to deliver the treatment energy
to modulate the nerve without damaging tissues that are within a path of the treatment
energy to the nerve.
[0077] In some embodiments, the nerve comprises a renal nerve, and the system further includes
a processor located outside the patient, wherein the processor is configured for receiving
an input related to a position of a renal artery, determining an output related to
a position of the renal nerve based on a model that associates artery position with
nerve position, and providing the output to a positioning system for the energy source
so that the positioning system can cause the energy source to deliver the treatment
energy from the outside of the patient to the renal nerve to treat the renal nerve.
[0078] In some embodiments, the system further includes a processor for determining a position
of a renal vessel located outside the patient.
[0079] In some embodiments, the system further includes an imaging device for providing
an image signal, wherein the processor is configured to determine the position based
on the image signal.
[0080] In some embodiments, the imaging device comprises a CT device, a MRI device, a thermography
device, an infrared imaging device, an optical coherence tomography device, a photoacoustic
imaging device, a PET imaging device, a SPECT imaging device, or an ultrasound device.
[0081] In some embodiments, the position of the renal vessel is used during the treatment
energy delivery to target the nerve that surrounds the renal vessel.
[0082] In some embodiments, the position is determined using a Doppler triangulation technique.
[0083] In some embodiments, the renal vessel comprises a renal artery.
[0084] In some embodiments, treatment energy is delivered to a kidney to decrease a sympathetic
stimulus to the kidney, decrease an afferent signal from the kidney to an autonomic
nervous system, or both.
[0085] In some embodiments, the energy source is also configured to deliver testing energy
to the patient to determine if there is a reaction resulted therefrom.
[0086] In some embodiments, the energy source is configured to deliver the treatment energy
to treat hypertension.
[0087] In some embodiments, the energy source is configured to deliver the treatment energy
to treat glaucoma.
[0088] In some embodiments, the energy source has an orientation so that the energy source
aims at a direction that aligns with a vessel that is next to the nerve.
[0089] In some embodiments, the energy source is configured to track a movement of the nerve.
[0090] In some embodiments, the energy source is configured to track the movement of the
nerve by tracking a movement of a blood vessel next to the nerve.
[0091] In some embodiments, the energy source is configured to aim at the nerve by aiming
at a vessel that is surrounded by the nerve.
[0092] In some embodiments, the system further includes a device for placement inside the
patient, and a processor for determining a position using the device, wherein the
energy source is configured to aim the energy delivery path towards the nerve inside
the patient based at least in part on the determined position.
[0093] In some embodiments, the device is sized for insertion into a vessel that is surrounded
by the nerve.
[0094] I n some embodiments, a system to deliver energy from a position outside a skin of
a patient to a nerve surrounding a blood vessel inside the patient, includes a processor
configured to receive image signal, and determine a three dimensional coordinate of
a blood vessel based on the image signal, and an energy source configured to deliver
energy from the position outside the skin of the patient to the nerve surrounding
the blood vessel, wherein the processor is also configured to control the energy source
based on the determined coordinate.
[0095] In some embodiments, the system further includes an imaging device for providing
the image signal.
[0096] In some embodiments, the imaging device comprises a MRI device.
[0097] In some embodiments, the imaging device comprises an ultrasound device.
[0098] In some embodiments, the energy comprises focused energy.
[0099] In some embodiments, the energy comprises focused ultrasound.
[0100] In some embodiments, the energy source comprises an ultrasound array that is aligned
with the vessel.
[0101] In some embodiments, the system further includes an imaging device for providing
a B-mode ultrasound for imaging the blood vessel.
[0102] In some embodiments, a system to deliver energy from a position outside a skin of
a patient to a nerve surrounding a blood vessel includes a fiducial for placement
inside the blood vessel, a detection device to detect the fiducial inside the blood
vessel, a processor configured to determine a three dimensional coordinate of the
detected fiducial, and an energy source configured to transmit energy through the
skin and to focus the energy at the region of the blood vessel, wherein the processor
is configured to operate the energy source based on the determined three dimensional
coordinate of the fiducial, and information regarding the blood vessel.
[0103] In some embodiments, the energy source comprises an ultrasound device, and wherein
the blood vessel is a renal artery.
[0104] In some embodiments, the system further includes an ultrasound imaging system.
[0105] In some embodiments, the fiducial is placed inside the blood vessel and is attached
to an intravascular catheter.
[0106] In some embodiments, the fiducial is a passive fidicial that is configured to respond
to an external signal.
[0107] In some embodiments, the fiducial is an active ficucial, transmitting its position
to the detection device.
[0108] In some embodiments, a method to treat hypertension in a patient includes obtaining
an imaging signal from a blood vessel in the patient, planning a delivery of energy
to a wall of the blood vessel, and delivering energy from outside a skin of the patient
to an autonomic nerve surrounding the blood vessel.
[0109] In some embodiments, the method further includes selectively modulating an afferent
nerve within a sympathetic nerve bundle.
[0110] In some embodiments, the method further includes utilizing microneurography after
the delivery of the energy to determine an effect of the energy delivery on a sympathetic
nervous system.
[0111] In some embodiments, the blood vessel extends to or from a kidney, and the method
further comprises locating the blood vessel with doppler ultrasound.
[0112] In some embodiments, a system to modulate an autonomic nerve in a patient utilizing
transcutaneous energy delivery, the system includes a processor comprising an input
for receiving information regarding energy and power to be delivered to a treatment
region containing the nerve, and an output for outputting a signal, wherein the processor
is configured to determine a position of a reference target from outside the patient
to localize the nerve relative to the reference target, a therapeutic energy device
comprising a transducer for delivering energy from outside the patient, a controller
to control an aiming of the transducer based at least in part on the signal from the
processor, and an imaging system coupled to the processor or the therapeutic energy
device.
[0113] In some embodiments, the processor is configured to determine the position during
an operation of the therapeutic energy device.
[0114] In some embodiments, the system further includes a patient interface configured to
position the therapeutic device so that the transducer is aimed toward a blood vessel
connected to a kidney from a position between ribs superiorly, a iliac crest inferiorly,
and a vertebral column medially.
[0115] In some embodiments, the therapeutic energy device is configured to deliver focused
ultrasound.
[0116] In some embodiments, the reference target is at least a portion of a blood vessel
traveling to or from a kidney, and the nerve is a renal nerve.
[0117] In some embodiments, the transducer is configured to focus energy at a distance from
6 cm to 18 cm.
[0118] In some embodiments, the transducer is configured to deliver the energy in a form
of focused ultrasound to a renal blood vessel at an angle ranging between about -10
degrees and about -48 degrees relative to a horizontal line connecting transverse
processes of a spinal column.
[0119] In some embodiments, the energy from the therapeutic energy device ranges between
100 W/cm2 and 2500 W/cm2.
[0120] In some embodiments, the reference target is an indwelling vascular catheter.
[0121] In some embodiments, the imaging system is a magnetic resonance imaging system and
the therapeutic energy device is an ultrasound device.
[0122] In some embodiments, the imaging system is an ultrasound imaging system.
[0123] In some embodiments, the processor is a part of the therapeutic energy device.
[0124] In some embodiments, the processor is a part of the imaging system.
[0125] In some embodiments, a method to deliver energy from a position outside the skin
of a patient to a nerve surrounding a blood vessel, includes placing a device inferior
to ribs, superior to an iliac crest, and lateral to a spine, and using the device
to maintain an energy delivery system at a desired position relative to the patient
so that the energy delivery system can deliver energy through the skin without traversing
bone.
[0126] In some embodiments, the energy delivery system comprises a focused ultrasound delivery
system.
[0127] In some embodiments, a device for use in a system to deliver focused ultrasound energy
from a position outside a skin of a patient to a nerve surrounding a blood vessel,
includes a positioning device configured to maintain an energy delivery system at
a desired position relative to the patient so that the energy delivery system can
deliver energy through the skin without traversing bone, wherein the positioning device
is configured to be placed inferior to ribs, superior to an iliac crest, and lateral
to a spine.
[0128] In some embodiments, the energy delivery system comprises a focused ultrasound delivery
system.
[0129] In some embodiments, the positioning device is configured to maintain an angle of
the focused ultrasound delivery system such that bony structures are not include in
an ultrasound field.
[0130] In some embodiments, a system for treatment includes a treatment device configured
to deliver energy from outside a patient to a nerve inside the patient, a catheter
configured for placement inside a vessel surrounded by the nerve, the catheter configured
to transmit a signal, and a processor configured to receive the signal and determine
a reference position in the vessel, wherein the treatment device is configured deliver
the energy to the nerve based on the determined reference position.
[0131] In some embodiments, the treatment device comprises an ultrasound device.
[0132] In some embodiments, a method of inhibiting the function of a nerve traveling with
an artery includes providing an external imaging modality to determine the location
of the artery of a patient, placing the artery in a first three dimensional coordinate
reference based on the imaging, placing or associating a therapeutic energy generation
source in the first three dimensional coordinate reference frame, modeling the delivery
of energy to the adventitial region of the artery or a region adjacent to the artery
where a nerve travels, delivering therapeutic energy from the therapeutic energy source,
from at least two different angles, through the skin of a patient, to intersect at
the artery or the region adjacent to the artery, and at least partially inhibiting
the function of the nerve traveling with the artery.
[0133] In some embodiments, the imaging modality is one of: ultrasound, MRI, and CT.
[0134] In some embodiments, the therapeutic energy is ultrasound.
[0135] In some embodiments, the artery is a renal artery.
[0136] In some embodiments, placing the artery in a three dimensional reference frame comprises
locating the artery using a doppler ultrasound signal.
[0137] In some embodiments, the method further includes utilizing a fiducial wherein the
fiducial is placed internal to the patient.
[0138] In some embodiments, said fiducial is temporarily placed in a position internal to
the patient.
[0139] In some embodiments, said fiducial is a catheter placed in the artery of the patient.
[0140] In some embodiments, said catheter is detectable using a radiofrequency signal and
said imaging modality is ultrasound.
[0141] In some embodiments, the therapeutic energy from the energy source is delivered in
a distribution along the length of the artery.
[0142] In some embodiments, the therapeutic energy is ionizing radiation.
[0143] In some embodiments, a system to inhibit the function of a nerve traveling with a
renal artery includes a detector to determine the location of the renal artery and
renal nerve from a position external to a patient, an ultrasound component to deliver
therapeutic energy through the skin from at least two directions to the nerve surrounding
the renal artery, a modeling algorithm comprising an input and an output, said input
to the modeling algorithm comprising a three dimensional coordinate space containing
a therapeutic energy source and the position of the renal artery in the three dimensional
coordinate space, and said output from the modeling algorithm comprising the direction
and energy level of the ultrasound component, a fiducial, locatable from a position
outside a patient, adapted to be temporarily placed in the artery of the patient and
communicate with the detector to determine the location of the renal artery in a three
dimensional reference frame, the information regarding the location transmittable
as the input to the model.
[0144] In some embodiments, the fiducial is a passive reflector of ultrasound.
[0145] In some embodiments, the fiducial generates radiofrequency energy.
[0146] In some embodiments, the fiducial is activated to transmit energy based on a signal
from an ultrasound or magnetic field generator.
[0147] In some embodiments, the output from the model instructs the ultrasound component
to deliver a lesion on the artery in which the major axis of the lesion is longitudinal
along the length of the artery.
[0148] In some embodiments, the output from the model instructs the ultrasound component
to deliver multiple lesions around an artery simultaneously.
[0149] In some embodiments, the output from the model instructs the ultrasound component
to deliver a circumferential lesion around the artery.
[0150] In some embodiments, the lesion is placed around the renal artery just proximal to
the bifurcation of the artery in the hilum of the kidney.
[0151] In some embodiments, a method to stimulate or inhibit the function of a nerve traveling
to or from the kidney includes identifying an acoustic window at the posterior region
of a patient in which the renal arteries can be visualized, transmitting a first energy
through the skin of a patient from the posterior region of the patient, imaging an
arterial region using the first transmitted energy, and applying a second transmitted
energy to the arterial adventitia by coupling the imaging and the second transmitted
energy.
[0152] In some embodiments, the method further includes tracking the image created by the
first transmitted energy.
[0153] In some embodiments, a method to locate the position of a blood vessel in the body
of a patient includes applying a first wave of ultrasound, from a first direction,
to a region of a blood vessel from outside of the patient and detecting its return
signal, comparing the applied first wave and its return signal, simultaneously, or
sequentially, applying a second wave of ultrasound from a second direction to the
blood vessel and detecting a its return signal, and integrating the return signals
from the first wave and the return signals from the second wave to determine the position,
in a three dimensional coordinate reference, of the blood vessel.
[0154] In some embodiments, the method further includes the step of instructing a therapeutic
ultrasound transducer to apply energy to the position of the blood vessel.
Description of Figures
[0155]
Figures 1a-b depict the focusing of energy sources on nerves of the autonomic nervous
system.
Figure 1c depicts an imaging system to help direct the energy sources.
Figure 2 depicts targeting and/or therapeutic ultrasound delivered through the stomach
to the autonomic nervous system posterior to the stomach.
Figure 3a depicts focusing of energy waves on the renal nerves.
Figure 3b depicts a coordinate reference frame for the treatment.
Figure 3C depicts targeting catheters placed in any of the renal vessels.
Figure 3D depicts an image detection system of a blood vessel with a temporary fiducial
placed inside.
Figure 3E depicts a therapy paradigm for the treatment and assessment of hypertension.
Figure 4a depicts the application of energy to the autonomic nervous system surrounding
the carotid arteries.
Figure 4B depicts the application of energy to through the vessels of the renal hilum.
Figs 5a-b depicts the application of focused energy to the autonomic nervous system
of the eye.
Fig. 6 depicts the application of constricting lesions to the kidney deep inside the
calyces of the kidney.
Figures 7a depicts a patient in an imaging system receiving treatment with focused
energy waves.
Figure 7b depicts visualization of a kidney being treated.
Figure 7c depicts a close up view of the renal nerve region of the kidney being treated.
Figure 7d depicts an algorithmic method to treat the autonomic nervous system using
MRI and energy transducers.
Figure 7e depicts a geometric model obtained from cross-sectional images of the area
of the aorta and kidneys.
Figure 7F depicts a close up image of the region of treatment.
Figure 7G depicts the results of measurements from a series of cross sectional image
reconstructions.
Figure 7H depicts the results of measurements from a series of cross-sectional images
from a patient in a more optimized position.
Figure 7I depicts an algorithmic methodology to apply treatment to the hilum of the
kidney and apply energy to the renal blood vessels.
Figure 8a depicts a percutaneous approach to treating the autonomic nervous system
surrounding the kidneys.
Figure 8b depicts an intravascular approach to treating or targeting the autonomic
nervous system.
Figure 8C depicts a percutaneous approach to the renal hila using a CT scan and a
probe to reach the renal blood vessels.
Figures 9a-c depicts the application of energy from inside the aorta to regions outside
the aorta to treat the autonomic nervous system.
Figure 10 depicts steps to treat a disease using HIFU while monitoring progress of
the treatment as well as motion.
Figure 11a depicts treatment of brain pathology using cross sectional imaging.
Figure 11b depicts an image on a viewer showing therapy of the region of the brain
being treated.
Figure 11c depicts another view of a brain lesion as might be seen on an imaging device
which assists in the treatment of the lesion.
Figure 12 depicts treatment of the renal nerve region using a laparoscopic approach.
Figure 13 depicts a methodology for destroying a region of tissue using imaging markers
to monitor treatment progress.
Figure 14 depicts the partial treatment of portions of a nerve bundle using converging
imaging and therapy wave.
Figure 15a-b depicts the application of focused energy to the vertebral column to
treat various spinal pathologies including therapy of the spinal or intravertebral
nerves.
Figure 16A depicts the types of lesions which are created around the renal arteries
to affect a response.
Figure 16B depicts a simulation of ultrasound around a blood vessel I support of Figure
16A.
Figure 16C depicts data from ultrasound energy applied to the renal blood vessels
and the resultant change in norepinephrine levels.
Figure 17A depicts the application of multiple transducers to treat regions of the
autonomic nervous system at the renal hilum.
Figures 17B-C depict methods for using imaging to direct treatment of a specific region
surrounding an artery as well as display the predicted lesion morphology.
Figure 17D depicts a method for localizing HIFU transducers relative to Doppler ultrasound
signals.
Figure 17E depicts an arrangement of transducers relative to a target.
Figure 17F depicts ablation zones in a multi-focal region in cross-section.
Figure 18 depicts the application of energy internally within the kidney to affect
specific functional changes at the regional level within the kidney.
Figure 19A depicts the direction of energy wave propagation to treat regions of the
autonomic nervous system around the region of the kidney hilum.
Figure 19B depicts a schematic of a B mode ultrasound from a direction determined
through experimentation to provide access to the renal hilum with HIFU.
Figure 20 depicts the application of ultrasound waves through the wall of the aorta
to apply a therapy to the autonomic nervous system.
Figure 21A depicts application of focused energy to the ciliary muscles and processes
of the anterior region of the eye.
Figure 21B depicts the application of focused non-ablative energy to the back of the
eye to enhance drug or gene delivery or another therapy such as ionizing radiation.
Figure 22 depicts the application of focused energy to nerves surrounding the knee
joint to affect nerve function in the joint.
Figures 23A-B depicts the application of energy to the fallopian tube to sterilize
a patient.
Figure 24 depicts an algorithm to assess the effect of the neural modulation procedure
on the autonomic nervous system. After a procedure is performed on the renal nerves,
assessment of the autonomic response is performed by, for example, simulating the
autonomic nervous system in one or more places.
Figure 25 depicts an optimized position of a device to apply therapy to internal nerves.
Figure 26A depicts positioning of a patient to obtain parameters for system design.
Figure 26B depicts a device design based on the information learned from feasibility
studies.
Figure 27 depicts a clinical paradigm for treating the renal nerves of the autonomic
nervous system based on feasibility studies.
Figure 28 A-C depicts a treatment positioning system for a patient incorporating a
focused ultrasound system.
Figure 29 A-D depicts results of studies applying focused energy to nerves surrounding
arteries and of ultrasound studies to visualize the blood vessels around which the
nerves travel.
Figure 29E depicts the results of design processes in which the angle, length, and
surface area from CT scans is quantified.
Figures 30A-I depicts results of simulations to apply focused ultrasound to the region
of a renal artery with a prototype device design based on simulations.
Detailed Description
[0156] Hypertension is a disease of extreme national and international importance. There
are 80 million patients in the US alone who have hypertension and over 200 million
in developed countries worldwide. In the United States, there are 60 million patients
who have uncontrolled hypertension, meaning that they are either non-compliant or
cannot take the medications because of the side effect profile. Up to 10 million people
might have completely resistant hypertension in which they do not reach target levels
no matter what the medication regimen. The morbidities associated with uncontrolled
hypertension are profound, including stroke, heart attack, kidney failure, peripheral
arterial disease, etc. A convenient and straightforward minimally invasive procedure
to treat hypertension would be a very welcome advance in the treatment of this disease.
[0157] Congestive Heart Failure ("CHF") is a condition which occurs when the heart becomes
damaged and blood flow is reduced to the organs of the body. If blood flow decreases
sufficiently, kidney function becomes altered, which results in fluid retention, abnormal
hormone secretions and increased constriction of blood vessels. These results increase
the workload of the heart and further decrease the capacity of the heart to pump blood
through the kidneys and circulatory system.
[0158] It is believed that progressively decreasing perfusion of the kidneys is a principal
non-cardiac cause perpetuating the downward spiral of CHF. For example, as the heart
struggles to pump blood, the cardiac output is maintained or decreased and the kidneys
conserve fluid and electrolytes to maintain the stroke volume of the heart. The resulting
increase in pressure further overloads the cardiac muscle such that the cardiac muscle
has to work harder to pump against a higher pressure. The already damaged cardiac
muscle is then further stressed and damaged by the increased pressure. Moreover, the
fluid overload and associated clinical symptoms resulting from these physiologic changes
result in additional hospital admissions, poor quality of life, and additional costs
to the health care system. In addition to exacerbating heart failure, kidney failure
can lead to a downward spiral and further worsening kidney function. For example,
in the forward flow heart failure described above, (systolic heart failure) the kidney
becomes ischemic. In backward heart failure (diastolic heart failure), the kidneys
become congested vis-Ã -vis renal vein hypertension. Therefore, the kidney can contribute
to its own worsening failure.
[0159] The functions of the kidneys can be summarized under three broad categories: filtering
blood and excreting waste products generated by the body's metabolism; regulating
salt, water, electrolyte and acid-base balance; and secreting hormones to maintain
vital organ blood flow. Without properly functioning kidneys, a patient will suffer
water retention, reduced urine flow and an accumulation of waste toxins in the blood
and body. These conditions result from reduced renal function or renal failure (kidney
failure) and are believed to increase the workload of the heart. In a CHF patient,
renal failure will cause the heart to further deteriorate as fluids are retained and
blood toxins accumulate due to the poorly functioning kidneys. The resulting hypertension
also has dramatic influence on the progression of cerebrovascular disease and stroke.
[0160] The autonomic nervous system is a network of nerves which affect almost every organ
and physiologic system to a variable degree. Generally, the system is composed of
sympathetic and parasympathetic nerves. For example, the sympathetic nerves to the
kidney traverse the sympathetic chain along the spine and synapse within the ganglia
of the chain or within the celiac ganglia, then proceeding to innervate the kidney
via post-ganglionic fibers inside the "renal nerves." Within the renal nerves, which
travel along the renal hila (artery and to some extent the vein), are the post-ganglionic
sympathetic nerves and the afferent nerves from the kidney. The afferent nerves from
the kidney travel within the dorsal root (if they are pain fibers)and into the anterior
root if they are sensory fibers, then into the spinal cord and ultimately to specialized
regions of the brain. The afferent nerves, baroreceptors and chemoreceptors, deliver
information from the kidneys back to the sympathetic nervous system via the brain;
their ablation or inhibition is at least partially responsible for the improvement
seen in blood pressure after renal nerve ablation, or dennervation, or partial disruption.
It has also been suggested and partially proven experimentally that the baroreceptor
response at the level of the carotid sinus is mediated by the renal artery afferent
nerves such that loss of the renal artery afferent nerve response blunts the response
of the carotid baroreceptors to changes in arterial blood pressure (
American J. Physioogy and Renal Physiology 279:F491-F501, 2000, incorporated by reference herein).
[0161] It has been established in animal models that the heart failure condition results
in abnormally high sympathetic activation of the kidneys. An increase in renal sympathetic
nerve activity leads to decreased removal of water and sodium from the body, as well
as increased renin secretion which stimulates aldosterone secretion from the adrenal
gland. Increased renin secretion can lead to an increase in angiotensin II levels
which leads to vasoconstriction of blood vessels supplying the kidneys as well as
systemic vasoconstriction, all of which lead to a decrease in renal blood flow and
hypertension. Reduction in sympathetic renal nerve activity, e.g., via de-innervation,
may reverse these processes and in fact has been shown to in the clinic. Similarly,
in obese patients, the sympathetic drive is intrinsically very high and is felt to
be one of the causes of hypertension in obese patients.
[0162] Recent clinical work has shown that de-innervation of the renal sympathetic chain
and other nerves which enter the kidney through the hilum can lead to profound systemic
effects in patients (rats, dogs, pig, sheep, humans) with hypertension, heart failure,
and other organ system diseases. Such treatment can lead to long term reduction in
the need for blood pressure medications and improvements in blood pressure (O'Brien
Lancet 2009 373; 9681 incorporated by reference). The devices used in this trial were
highly localized radiofrequency (RF) ablation to ablate the renal artery adventitia
with the presumption that the nerves surrounding the renal artery are being inhibited
in the heating zone as well. The procedure is performed in essentially a blind fashion
in that the exact location of the nerve plexus is not known prior to, during, or after
the procedure. In addition, the wall of the renal artery is invariably damaged by
the RF probe and patients whose vessels have a great deal of atherosclerosis cannot
be treated safely. In addition, depending on the distance of the nerves from the vessel
wall, the energy may not consistently lead to ablation or interruption. Finally, the
use of internal catheters may not allow for treatment inside the kidney or inside
the aorta if more selective. In many cases, it is required to create a spiral along
the length and inside the blood vessel to avoid circumferential damage to the vessel.
[0163] Cross-sectional imaging can be utilized to visualize the internal anatomy of patients
via radiation (CT) or magnetic fields (MRI). Ultrasound can also be utilized to obtain
cross-sections of specific regions but only at high frequencies; therefore, ultrasound
is typically limited to imaging superficial body regions. CT and MRI are often more
amenable to cross sectional imaging because the radiation penetrates well into tissues.
In addition, the scale of the body regions is maintained such that the anatomy within
the coordinate references remains intact relative to one another; that is, distances
between structures can be measured.
[0164] With ultrasound, scaling can be more difficult because of unequal penetration as
the waves propagate deeper through the tissue. CT scans and MRIs and even ultrasound
devices can be utilized to create three dimensional representations and reconstructed
cross-sectional images of patients; anatomy can be placed in a coordinate reference
frame using a three dimensional representation. Once in the reference frame, energy
devices (transducers) can be placed in position and energy emitting devices directed
such that specific regions of the body are targeted. Once knowledge of the transducer
position is known relative to the position of the target in the patient body, energy
can be delivered to the target.
[0165] Ultrasound is a cyclically generated sound pressure wave with a frequency greater
than the upper limit of human hearing...20 kilohertz (kHz). In medicine, ultrasound
is widely utilized because of its ability to penetrate tissues. Reflection of the
sound waves reveals a signature of the underlying tissues and as such, ultrasound
can be used extensively for diagnostics and potentially therapeutics as well in the
medical field. As a therapy, ultrasound has the ability to both penetrate tissues
and can be focused to create ablation zones. Because of its simultaneous ability to
image, ultrasound can be utilized for precise targeting of lesions inside the body.
Ultrasound intensity is measured by the power per cm
2 (for example, W/cm
2 at the therapeutic target region). Generally, high intensity refers to intensities
over 0.1 - 5kW/cm
2. Low intensity ultrasound encompasses the range up to 0.01 - .10 kW/cm
2 from about 1 or 10 Watts per cm
2.
[0166] Ultrasound can be utilized for its forward propagating waves and resulting reflected
waves or where energy deposition in the tissue and either heating or slight disruption
of the tissues is desired. For example, rather than relying on reflections for imaging,
lower frequency ultrasonic beams (e.g. < 1 MHz) can be focused at a depth within tissue,
creating a heating zone or a defined region of cavitation in which micro-bubbles are
created, cell membranes are opened to admit bioactive molecules, or damage is otherwise
created in the tissue. These features of ultrasound generally utilize frequencies
in the 0.25 Megahertz (MHz) to 10 MHz range depending on the depth required for effect.
Focusing is, or may be, required so that the surface of the tissue is not excessively
injured or heated by single beams. In other words, many single beams can be propagated
through the tissue at different angles to decrease the energy deposition along any
single path yet allow the beams to converge at a focal spot deep within the tissue.
In addition, reflected beams from multiple angles may be utilized in order to create
a three dimensional representation of the region to be treated in a coordinate space.
[0167] It is important when planning an ultrasound therapy that sharp, discontinuous interfaces
be avoided. For example, bowel, lung, bone which contain air and/or bone interfaces
constitute sharp boundaries with soft tissues. These interfaces make the planning
and therapy more difficult. If however, the interfaces can be avoided, then treatment
can be greatly simplified versus what has to done for the brain (e.g. MR-guided HIFU)
where complex modeling is required to overcome the very high attenuation of the cranium.
Data provided below reveals a discovery through extensive experimentation as to how
to achieve this treatment simplicity.
[0168] Time of flight measurements with ultrasound can be used to range find, or find distances
between objects in tissues. Such measurements can be utilized to place objects such
as vessels into three dimensional coordinate reference frames so that energy can be
utilized to target the tissues. SONAR is the acronym for sound navigation and ranging
and is a method of acoustic localization. Sound waves are transmitted through a medium
and the time for the sound to reflect back to the transmitter is indicative of the
position of the object of interest. Doppler signals are generated by a moving object.
The change in the forward and reflected wave results in a velocity for the object.
[0169] The concept of speckle tracking is one in which the reflections of specific tissues
is defined and tracked over time (
IEEE Transactions on Ultrasonics, Ferroelectrics, AND Frequency Control, Vol. 57,
no. 4, April 2010, herein incorporated by reference). With defined points in space, a three dimensional
coordinate reference can be created through which energy can be applied to specific
and well-defined regions. To track a speckle, an ultrasound image is obtained from
a tissue. Light and dark spots are defined in the image, these light and dark spots
representing inhomgeneities in the tissues. The inhomegeneities are relatively constant,
being essentially properties of the tissue. With relatively constant markers in the
tissue, tracking can be accomplished using real time imaging of the markers. With
more than one plane of ultrasound, the markers can be related in three dimensions
relative to the ultrasound transducer and a therapeutic energy delivered to a defined
position within the three dimensional field.
[0170] At the time one or more of these imaging modalities is utilized to determine the
position of the target in three dimensions, then a therapy can be both planned and
applied to a specific region within the three dimensional volume.
[0171] Lithotripsy was introduced in the early part of the 1980's. Lithotripsy utilizes
shockwaves to treat stones in the kidney. The Dornier lithotripsy system was the first
system produced for this purpose. The lithotripsy system sends ultrasonic waves through
the patient's body to the kidney to selectively heat and vibrate the kidney stones;
that is, selectively over the adjacent tissue. At the present time, lithotripsy systems
do not utilize direct targeting and imaging of the kidney stone region. A tremendous
advance in the technology
would be to image the stone region and target the specific region in which the stone resides
so as to minimize damage to surrounding structures such as the kidney. In the case
of a kidney stone, the kidney is in fact the speckle, allowing for three dimensional
targeting and tracking off its image with subsequent application of ultrasound waves
to break up the stone. In the embodiments which follow below, many of the techniques
and imaging results described can be applied to clinical lithotripsy.
[0172] Histotripsy is a term given to a technique in which tissue is essentially vaporized
using cavitation rather than heating (transcutaneous non-thermal mechanical tissue
fractionation). These mini explosions do not require high temperature and can occur
in less than a second. The generated pressure wave is in the range of megapascals
(MPa) and even up to or exceeding 100 MPa. To treat small regions of tissue very quickly,
this technique can be very effective. The border of the viable and non-viable tissue
is typically very sharp and the mechanism of action has been shown to be cellular
disruption.
[0173] In one embodiment, ultrasound is focused on the region of the renal arteries and/or
veins from outside the patient; the ultrasound is delivered from multiple angles to
the target, thereby overcoming many of the deficiencies in previous methods and devices
put forward to ablate renal sympathetic nerves which surround the renal arteries.
[0174] Specifically, one embodiment allows for precise visualization of the ablation zone
so that the operator can be confident that the correct region is ablated and that
the incorrect region is not ablated. Because some embodiments do not require a puncture
in the skin, they are considerably less invasive, which is more palatable and safer
from the patient standpoint. Moreover, unusual anatomies and atherosclerotic vessels
can be treated using external energy triangulated on the renal arteries to affect
the sympathetic and afferent nerves to and from the kidney respectively.
[0175] With reference to FIG. 1A, the human renal anatomy includes the kidneys 100 which
are supplied with oxygenated blood by the renal arteries 200 and are connected to
the heart via the abdominal aorta 300. Deoxygenated blood flows from the kidneys to
the heart via the renal veins (not shown) and thence the inferior vena cava (not shown).
The renal anatomy includes the cortex, the medulla, and the hilum. Blood is delivered
to the cortex where it filters through the glomeruli and is then delivered to the
medulla where it is further filtered through a series of reabsorption and filtration
steps in the loops of henle and individual nephrons; the ultrafiltrate then percolates
to the ureteral collecting system and is delivered to the ureters and bladder for
ultimate excretion.
[0176] The hila is the region where the major vessels (renal artery and renal vein) and
nerves 150 (efferent sympathetic, afferent sensory, and parasympathetic nerves) travel
to and from the kidneys. The renal nerves 150 contain post-ganglionic efferent nerves
which supply sympathetic innervation to the kidneys. Afferent sensory nerves travel
from the kidney to the central nervous system and are postganglionic afferent nerves
with nerve bodies in the central nervous system. These nerves deliver sensory information
to the central nervous system and are thought to regulate much of the sympathetic
outflow from the central nervous system to all organs including the skin, heart, kidneys,
brain, etc.
[0177] In one method, energy is delivered from outside a patient, through the skin, and
to the renal afferent and/or renal efferent nerves. Microwave, light, vibratory (e.g.
acoustic), ionizing radiation might be utilized in some or many of the enbodiments.
[0178] Energy transducers 510 (figure 1 A) deliver energy transcutaneously to the region
of the sympathetic ganglia 520 or the post-ganglionic renal nerves 150 or the nerves
leading to the adrenal gland 400. The energy is generated from outside the patient,
from multiple directions, and through the skin to the region of the renal nerves 624
which surround the renal artery 620 or the sumpathetic ganglion 622 which house the
nerves. The energy can be focused or non-focused but in one preferred embodiment,
the energy is focused with high intensity focused ultrasound (HIFU) or low intensity
focused ultrasound.
[0179] Focusing with low intensity focused ultrasound (LIFU) may also occur intentionally
as a component of the HIFU (penumbra regions) or unintentionally. The mechanism of
nerve inhibition is variable depending on the "low" or "high" of focused ultrasound.
Low energy might include energies levels of 25W/cm
2-200W/cm
2. Higher intensity includes energy levels from 200 W/cm
2 to 1 MW/cm
2. Focusing occurs by delivering energy from at least two different angles through
the skin to meet at a focal point where the highest energy intensity and density occurs.
At this spot, a therapy is delivered and the therapy can be sub-threshold nerve interruption
(partial ablation), ablation (complete interruption) of the nerves, controlled interruption
of the nerve conduction apparatus, partial ablation, or targeted drug delivery. The
region can be heated to a temperature of less than 60 degrees Celsius for non-ablative
therapy or can be heated greater than 60 degrees Celsius for heat based destruction
(ablation). To ablate the nerves, even temperatures in the 40 degree Celsius range
can be used and if generated for a time period greater than several minutes, will
result in ablation. For temperatures at about 50 degrees Celsius, the time might be
under one minute. Heating aside, a vibratory effect for a much shorter period of time
at temperatures below 60 degrees Celsius can result in partial or complete paralysis
of destruction of the nerves. If the temperature is increased beyond 50-60 degrees
Celsius, the time required for heating is decreased considerably to affect the nerve
via the sole mechanism of heating. In some embodiments, an imaging modality is included
as well in the system. The imaging modality can be ultrasound based, MRI based, or
CT (X-Ray) based. The imaging modality can be utilized to target the region of ablation
and determined the distances to the target.
[0180] The delivered energy can be ionizing or non-ionizing energy in some embodiments.
Forms of non-ionizing energy can include electromagnetic energy such as a magnetic
field, light, an electric field, radiofrequency energy, and light based energy. Forms
of ionizing energy include x-ray, proton beam, gamma rays, electron beams, and alpha
rays. In some embodiments, the energy modalities are combined. For example, heat ablation
of the nerves is performed and then ionizing radiation is delivered to the region
to prevent re-growth of the nerves.
[0181] Alternatively, ionizing radiation is applied first as an ablation modality and then
heat applied afterward in the case of re-growth of the tissue as re-radiation may
not be possible (complement or multimodality energy utilization). Ionizing radiation
may prevent or inhibit the re-growth of the nervous tissue around the vessel if there
is indeed re-growth of the nervous tissue. Therefore, another method of treating the
nerves is to first heat the nerves and then apply ionizing radiation to prevent re-growth.
[0182] Other techniques such as photodynamic therapy including a photosensitizer and light
source to activate the photosensitizer can be utilized as a manner to combine modalities.
Most of these photosensitizing agents are also sensitive to ultrasound energy yielding
the same photoreactive species as if it were activated by light. A photoreactive or
photosensitive agent can be introduced into the target area prior to the apparatus
being introduced into the blood vessel; for example, through an intravenous injection,
a subcutaneous injection, etc.. However, it will be understood that if desired, the
apparatus can optionally include a lumen for delivering a photoreactive agent into
the target area. The resulting embodiments are likely to be particularly beneficial
where uptake of the photoreactive agent into the target tissues is relatively rapid,
so that the apparatus does not need to remain in the blood vessel for an extended
period of time while the photoreactive agent is distributed into and absorbed by the
target tissue.
[0183] Light source arrays can include light sources that provide more than one wavelength
or waveband of light. Linear light source arrays are particularly useful to treat
elongate portions of tissue. Light source arrays can also include reflective elements
to enhance the transmission of light in a preferred direction. For example, devices
can beneficially include expandable members such as inflatable balloons to occlude
blood flow (which can interfere with the transmission of light from the light source
to the intended target tissue) and to enable the apparatus to be centered in a blood
vessel. Another preferred embodiment contemplates a transcutaneous PDT method where
the photosensitizing agent delivery system comprises a liposome delivery system consisting
essentially of the photosensitizing agent.
[0184] Yet another embodiment of the present invention is drawn to a method for transcutaneous
ultrasonic therapy of a target lesion in a mammalian subject utilizing a sensitizer
agent. In this embodiment, the biochemical compound is activated by ultrasound through
the following method:
- 1) administering to the subject a therapeutically effective amount of an ultrasonic
sensitizing agent or a ultrasonic sensitizing agent delivery system or a prodrug,
where the ultrasonic sensitizing agent or ultrasonic sensitizing agent delivery system
or prodrug selectively binds to the thick or thin neointimas, nerve cells, nerve sheaths,
nerve nuclei, arterial plaques, vascular smooth muscle cells and/or the abnormal extracellular
matrix of the site to be treated. Nerve components can also be targeted, for example,
the nerve sheath, myelin, S-100 protein. This step is followed by irradiating at least
a portion of the subject with ultrasonic energy at a frequency that activates the
ultrasonic sensitizing agent or if a prodrug, by a prodrug product thereof, where
the ultrasonic energy is provided by an ultrasonic energy emitting source. This embodiment
further provides, optionally, that the ultrasonic therapy drug is cleared from non-target
tissues of the subject prior to irradiation.
[0185] A preferred embodiment of this invention contemplates a method for transcutaneous
ultrasonic therapy of a target tissue, where the target tissue is close to a blood
vessel.
[0186] Other preferred embodiments of this invention contemplate that the ultrasonic energy
emitting source is external to the patient's intact skin layer or is inserted underneath
the patient's intact skin layer, but is external to the blood vessel to be treated.
An additional preferred embodiment t of this invention provides that the ultrasonic
sensitizing agent is conjugated to a ligand and more preferably, where the ligand
is selected from the group consisting of: a target lesion specific antibody; a target
lesion specific peptide and a target lesion specific polymer. Other preferred embodiments
of the present invention contemplate that the ultrasonic sensitizing agent is selected
from the group consisting of: indocyanine green (ICG); methylene blue; toluidine blue;
aminolevulinic acid (ALA); chlorin compounds; phthalocyanines; porphyrins; purpurins;
texaphyrins; and any other agent that absorbs light in a range of 500 nm-1100 nm.
A preferred embodiment of this invention contemplates that the photosensitizing agent
is indocyanine green (ICG).
[0187] Other embodiments of the present invention are drawn to the presently disclosed methods
of transcutaneous PDT, where the light source is positioned in proximity to the target
tissue of the subject and is selected from the group consisting of: an LED light source;
an electroluminesent light source; an incandescent light source; a cold cathode fluorescent
light source; organic polymer light source; and inorganic light source. A preferred
embodiment includes the use of an LED light source.
[0188] Yet other embodiments of the presently disclosed methods are drawn to use of light
of a wavelength that is from about 500 nm to about 1100 nm, preferably greater than
about 650 nm and more preferably greater than about 700 nm. A preferable embodiment
of the present method is drawn to the use of light that results in a single photon
absorption mode by the photosensitizing agent.
[0189] Additional embodiments of the present invention include compositions of photosensitizer
targeted delivery system comprising: a photosensitizing agent and a ligand that binds
a receptor on the target tissue with specificity. Preferably, the photosensitizing
agent of the targeted delivery system is conjugated to the ligand that binds a receptor
on the target (nerve or adventitial wall of blood vessel) with specificity. More preferably,
the ligand comprises an antibody that binds to a receptor. Most preferably, the receptor
is an antigen on thick or thin neointimas, intimas, adventitiaof arteries, arterial
plaques, vascular smooth muscle cells and/or the extracellular matrix of the site
to be treated.
[0190] A further preferred embodiment of this invention contemplates that the photosensitizing
agent is selected from the group consisting of: indocyanine green (ICG); methylene
blue; toluidine blue; aminolevulinic acid (ALA); chlorin compounds; phthalocyanines;
porphyrins; purpurins; texaphyrins; and any other agent that absorbs light in a range
of 500 nm -1100 nm.
[0191] Other photosensitizers of the present invention are known in the art, including,
photofrin. RTM, synthetic diporphyrins and dichlorins, phthalocyanines with or without
metal substituents, chloroaluminum phthalocyanine with or without varying substituents,
chloroaluminum sulfonated phthalocyanine, O-substituted tetraphenyl porphyrins, 3,1-meso
tetrakis (o-propionamido phenyl) porphyrin, verdins, purpurins, tin and zinc derivatives
of octaethylpurpurin, etiopurpurin, hydroporphyrins, bacteriochlorins of the tetra(hydroxyphenyl)
porphyrin series, chlorins, chlorin e6, mono-1-aspartyl derivative of chlorin e6,
di-I-aspartyl derivative of chlorin e6, tin(IV) chlorin e6, meta-tetrahydroxphenylchlorin,
benzoporphyrin derivatives, benzoporphyrin monoacid derivatives, tetracyanoethylene
adducts of benzoporphyrin, dimethyl acetylenedicarboxylate adducts of benzoporphyrin,
Diels-Adler adducts, monoacid ring "a" derivative of benzoporphyrin, sulfonated aluminum
PC, sulfonated AIPc, disulfonated, tetrasulfonated derivative, sulfonated aluminum
naphthalocyanines, naphthalocyanines with or without metal substituents and with or
without varying substituents, zinc naphthalocyanine, anthracenediones, anthrapyrazoles,
aminoanthraquinone, phenoxazine dyes, phenothiazine derivatives, chalcogenapyrylium
dyes, cationic selena and tellurapyrylium derivatives, ring-substituted cationic PC,
pheophorbide derivative, pheophorbide alpha and ether or ester derivatives, pyropheophorbides
and ether or ester derivatives, naturally occurring porphyrins, hematoporphyrin, hematoporphyrin
derivatives, hematoporphyrin esters or ethers, protoporphyrin, ALA-induced protoporphyrin
IX, endogenous metabolic precursors, 5-aminolevulinic acid benzonaphthoporphyrazines,
cationic imminium salts, tetracyclines, lutetium texaphyrin, tin-etio-purpurin, porphycenes,
benzophenothiazinium, pentaphyrins, texaphyrins and hexaphyrins, 5-amino levulinic
acid, hypericin, pseudohypericin, hypocrellin, terthiophenes, azaporphyrins, azachlorins,
rose bengal, phloxine B, erythrosine, iodinated or brominated derivatives of fluorescein,
merocyanines, nile blue derivatives, pheophytin and chlorophyll derivatives, bacteriochlorin
and bacteriochlorophyll derivatives, porphocyanines, benzochlorins and oxobenzochlorins,
sapphyrins, oxasapphyrins, cercosporins and related fungal metabolites and combinations
thereof.
[0193] In a preferred embodiment, the photosensitizer is tin ethyl etiopurpurin, commercially
known as purlytin (available from Miravant).
[0194] In some embodiments, external neuromodulation is performed in which low energy ultrasound
is applied to the nerve region to modulate the nerves. For example, it has been shown
in the past that low intensity (e.g. non-thermal) ultrasound can affect nerves at
powers which range from 30-500 mW/Cm
2 whereas HIFU (thermal modulation), by definition generates heat at a focus, requires
power levels exceeding 1000 W/Cm
2. The actual power flux to the region to be ablated is dependent on the environment
including surrounding blood flow and other structures. With low intensity ultrasound,
the energy does not have to be so strictly focused to the target because it's a non-ablative
energy; that is, the vibration or mechanical pressure may be the effector energy and
the target may have a different threshold for effect depending on the tissue. However,
even low energy ultrasound may require focusing if excessive heat to the skin is a
worry or if there are other susceptible structures in the path and only a pinpoint
region of therapy is desired. Nonetheless, transducers 500 in Figure 1 a provide the
ability to apply a range of different energy and power levels as well as modeling
capability to target different regions and predict the response.
[0195] In figure 1a, and in one embodiment, a renal artery 640 is detected with the assistance
of imaging devices 600 such as Doppler ultrasound, infrared imaging, thermal imaging,
B-mode ultrasound, MRI, or a CT scan. With an image of the region to be treated, measurements
in multiple directions on a series of slices can be performed so as to create a three-dimensional
representation of the area of interest. By detecting the position of the renal arteries
from more than one angle via Doppler triangulation (for example) or another triangulation
technique, a three dimensional positional map can be created and the renal artery
can be mapped into a coordinate reference frame. In this respect, given that the renal
nerves surround the renal blood vessels in the hilum, locating the direction and lengths
of the blood vessels in three dimensional coordinate reference is the predominant
component of the procedure to target these sympathetic nerves. Within the three dimensional
reference frame, a pattern of energy can be applied to the vicinity of the renal artery
from a device well outside the vicinity (and outside of the patient altogether) based
on knowledge of the coordinate reference frame.
[0196] For example, once the renal artery is placed in the coordinate reference frame with
the origin of the energy delivery device, an algorithm is utilized to localize the
delivery of focused ultrasound to heat or apply mechanical energy to the adventitia
and surrounding regions of the artery which contain sympathetic nerves to the kidney
and afferent nerves from the kidney, thereby decreasing the sympathetic stimulus to
the kidney and decreasing its afferent signaling back to the autonomic nervous system;
affecting these targets will modulate the propensity toward hypertension which would
otherwise occur. The ultrasonic energy delivery can be modeled mathematically by predicting
the acoustic wave dissipation using the distances and measurements taken with the
imaging modalities of the tissues and path lengths.
[0197] In one embodiment of an algorithm, the Doppler signal from the artery is identified
from at least two different directions and the direction of the artery is reconstructed
in three dimensional space. With two points in space, a line is created and with knowledge
of the thickness of the vessel, a tube, or cylinder, can be created to represent the
blood vessel as a virtual model. The tube is represented in three dimensional space
over time and its coordinates are known relative to the therapeutic transducers outside
of the skin of the patient. Therapeutic energy can be applied from more than one direction
as well and can focus on the cylinder (blood anterior vessel wall, central axis, or
posterior wall).
[0198] Focused energy (e.g. ultrasound) can be applied to the center of the vessel (within
the flow), on the posterior wall of the vessel, in between (e.g. when there is a back
to back artery and vein next to one another) the artery vessel and a venous vessel,
etc.
[0199] Imaging 600 of the sympathetic nerves or the sympathetic region (the target) is also
utilized so as to assess the direction and orientation of the transducers relative
to the target 620; the target is an internal fiducial, which in one embodiment is
the kidney 610 and associated renal artery 620 because they can be localized via thier
blood flow, a model then produced around it, and then they both can be used as a target
for the energy. Continuous feedback of the position of the transducers 500,510 relative
to the target 620 is provided by the imaging system in which the coordinate space
of the imaging system. The imaging may be a cross-sectional imaging technology such
as CT or MRI or it may be an ultrasound imaging technology which yields faster real
time imaging. In some embodiments, the imaging may be a combination of technologies
such as the fusion of MRI/CT and ultrasound. The imaging system can detect the position
of the target in real time at frequencies ranging from 1 Hz to thousands and tens
of thousands of images per second.
[0200] In the example of fusion, cross-sectional imaging (e.g. MRI/CT) is utilized to place
the body of the patient in a three dimensional coordinate frame and then ultrasound
is linked to the three dimensional reference frame and utilized to track the patient's
body in real time under the ultrasound linked to the cross-sectional imaging. The
lack of resolution provided by the ultrasound is made up for by the cross-sectional
imaging since only a few consistent anatomic landmarks are required for an ultrasound
image to be linked to the MRI image. As the body moves under the ultrasound, the progressively
new ultrasound images are linked to the MRI images and therefore MRI "movement" can
be seen at a frequency not otherwise available to an MRI series.
[0201] In one embodiment, ultrasound is the energy used to inhibit nerve conduction in the
sympathetic nerves. In one embodiment, focused ultrasound (HIFU) from outside the
body through the skin is the energy used to inhibit sympathetic stimulation of the
kidney by delivering waves from a position external to the body of a patient and focusing
the waves on the sympathetic nerves on the inside of the patient and which surround
the renal artery of the patient.
[0202] As is depicted in Figure 3a-b, transducers 900 can emit ultrasound energy from a
position outside the patient to the region of the renal sympathetic nerves at the
renal pedicle 200. As shown in figure 1a, an image of the renal artery 620 using an
ultrasound, MRI, or CT scan can be utilized to determine the position of the kidney
610 and the renal artery 620 target. Doppler ultrasound can be used to determine the
location and direction of a Doppler signal from an artery and place the vessel into
a three dimensional reference frame 950, thereby enabling the arteries 200 and hence
the sympathetic nerves 220 (Figure 3a) around the artery to be much more visible so
as to process the images and then utilize focused external energy to pinpoint the
location and therapy of the sympathetic nerves. In this embodiment, ultrasound is
likely the most appropriate imaging modality.
[0203] Figure 1a also depicts the delivery of focused energy to the sympathetic nerve trunks
and ganglia 622 which run along the vertebral column and aorta 300; the renal artery
efferent nerves travel in these trunks and synapse to ganglia within the trunks. In
another embodiment, ablation of the dorsal and ventral roots at the level of the ganglia
or dorsal root nerves at T9-T11 (through which the afferent renal nerves travel) would
produce the same or similar effect to ablation at the level of the renal arteries.
[0204] In another embodiment, figure 1b illustrates the application of ionizing energy to
the region of the sympathetic nerves on the renal arteries 620 and/or renal veins.
In general, energy levels of greater than 20 Gy (Gray) are required for linear accelerators
or low energy x-ray machines to ablate nervous tissue using ionizing energy; however,
lower energy is required to stun, inhibit nervous tissue, or prevent re-growth of
nervous tissue; in some embodiment, ionizing energy levels as low as 2-5 Gy or 5-10
Gy or 10-15 Gy are delivered in a single or fractionated doses.
[0205] Combinations of ionizing energy and other forms of energy can be utilized in this
embodiment as well so as to prevent re-growth of the nervous tissue. For example,
a combination of heat and/or vibration and/or cavitation and/or ionizing radiation
might be utilized to prevent re-growth of nervous tissue after the partial or full
ablation of the nervous tissue surrounding the renal artery.
[0206] Figure 2 illustrates the renal anatomy and surrounding anatomy with greater detail
in that organs such as the stomach 700 are shown in its anatomic position overlying
the abdominal aorta 705 and renal arteries 715. In this embodiment, energy is delivered
through the stomach to reach an area behind the stomach. In this embodiment, the stomach
is utilized as a conduit to access the celiac ganglion 710, a region which would otherwise
be difficult to reach. The aorta 705 is shown underneath the stomach and the celiac
ganglion 710 is depicted surrounding the superior mesenteric artery and aorta. A transorally
placed tube 720 is placed through the esophagus and into the stomach. The tube overlies
the celiac ganglion when placed in the stomach and can therefore be used to deliver
sympatholytic devices or pharmaceuticals which inhibit or stimulate the autonomic
celiac ganglia behind the stomach; these therapies would be delivered via transabdominal
ultrasound or fluoroscopic guidance (for imaging) through the stomach. Similar therapies
can be delivered to the inferior mesenteric ganglion, renal nerves, or sympathetic
nerves traveling along the aorta through the stomach or other portion of the gastrointestinal
tract. The energy delivery transducers 730,731 are depicted external to the patient
and can be utilized to augment the therapy being delivered through the stomach to
the celiac ganglion. Alternatively, the energy delivery transducers can be utilized
for imaging the region of therapy.
[0207] In one embodiment, energy is applied to the region of the celiac ganglion from a
region outside the patient. In this embodiment, fluid is placed into the gastrointestinal
system, such as for example, in the stomach or small intestine. Ultrasound can then
be transmitted through the gastrointestinal organs to the ganglia of interest behind
the stomach.
[0208] Temporary neurostimulators can also be placed through the tube, such as, for example,
in an ICU setting where temporary blockage of the autonomic ganglia may be required.
Temporary neurostimulators can be used to over pace the celiac ganglion nerve fibers
and inhibit their function as a nerve synapse. Inhibition of the celiac ganglion may
achieve a similar function as ablation or modulation of the sympathetic nerves around
the renal arteries. That is, the decrease in the sympathetic activity to the kidneys
(now obtained with a more proximal inhibition) leads to the lowering of blood pressure
in the patient by decreasing the degree of sympathetic outflow from the sympathetic
nerve terminals. In the celiac ganglia, the blood pressure lowering effect is more
profound given that the celiac ganglia are pre-ganglionic and have more nerve fibers
to a greater number of regions than each renal nerve. The effect is also likely more
permanent than the effect on the post-ganglionic nerve fibers.
[0209] Fig. 3a illustrates the renal anatomy more specifically in that the renal nerves
220 extending longitudinally along the renal artery 200, are located generally within,
or just outside the adventitia, of the outer portion of the artery. Arteries are typically
composed of three layers: the first is the intimal, the second is the media, and the
third is the adventitia. The outer layer, the adventitia, is a fibrous tissue which
contains blood vessels and nerves. The renal nerves are generally postganglionic sympathetic
nerves although there are some ganglia which exist distal to the takeoff from the
aorta such that some of the nerve fibers along the renal artery are in fact pre-ganglionic.
By the time the fibers reach the kidney, the majority of the fibers are post-ganglionic.
The afferent nerves on the other hand leave the kidney and are post-ganglionic up
to the level of the brain. These fibers do no re-grow as quickly as the efferent fibers,
if at all.
[0210] Energy generators 900 deliver energy to the renal nerves accompanying the renal artery,
depositing energy from multiple directions to target inhibition of the renal nerve
complex. The energy generators can deliver ultrasound energy, ionizing radiation,
light (photon) therapy, or microwave energy to the region. The energy can be non-focused
in the case where a pharmaceutical agent is targeted to the region to be ablated or
modulated. Preferably, however, the energy is focused, being applied from multiple
angles from outside the body of the patient to reach the region of interest (e.g.
sympathetic nerves surrounding blood vessels). The energy transducers 900 are placed
in an X-Y-Z coordinate reference frame 950, as are the organs such as the kidneys.
The x-y-z coordinate frame is a real space coordinate frame. For example, real space
means that the coordinate reference is identifiable in the physical world; like a
GPS (global positioning system), with the physical coordinates, a physical object
can be located. Once in the x-y-z coordinate reference frame, cross-sectional imaging
using MRI, CT scan, and/or ultrasound is utilized to couple the internal anatomy to
the energy transducers. These same transducers may be utilized for the determination
of the reference point as well as the therapy. The transducers 900 in this embodiment
are focused on the region of the renal nerves at the level of the renal blood vessels,
the arteries and veins 200. The focus of the beams can be inside the artery, inside
the vein, on the adventitia of the artery or adventitia of the vein.
[0211] When applying ultrasonic energy across the skin to the renal artery region, energy
densities of potentially over 1 MW/cm
2 might be required at region of interest in the adventitia of the blood vessel. Typically,
however, power densities of 100 W/cm
2 to 3 kW/cm
2 would be expected to create the heating required to inhibit these nerves (see
Foley et. al. Image-Guided HIFU Neurolysis of Peripheral Nerves To Treat Spasticity
And Pain; Ultrasound in Med & Biol. Vol 30 (9) p 1199-1207 herein incorporated by reference). The energy may be pulsed across the skin in an
unfocused manner; however, for application of heat, the transducers must be focused
otherwise the skin and underlying tissues will receive too much heat. Under imaging
with MRI, temperature can be measured with the MRI image. When low energy ultrasound
is applied to the region, energy (power) densities in the range of 50 mW/cm
2 to 500 mW/cm
2 may be applied. Low energy ultrasound may be enough to stun or partially inhibit
the renal nerves particularly when pulsed and depending on the desired clinical result.
High intensity ultrasound applied to the region with only a few degrees of temperature
rise may have the same effect and this energy range may be in the 0.1 kW/cm2 to the
500 kW/cm2 range. A train of pulses also might be utilized to augment the effect on
nervous tissue. For example, a train of 100 short pulses, each less than a second
and applying energy densities of 1W/cm
2 to 500 W/cm
2. In some of the embodiments, cooling may be applied to the skin if the temperature
rise is deemed too large to be acceptable. Alternatively, the ultrasound transducers
can be pulsed or can be alternated with another set of transducers to effectively
spread the heat across the surface of the skin. In some embodiments, the energy is
delivered in a pulsed fashion to further decrease the risk to the intervening tissues
between the target and the transducer. The pulses can be as close as millisecond,
as described, or as long as hours, days or years.
[0212] In one method of altering the physiologic process of renal sympathetic excitation,
the region around the renal arteries is imaged using CT scan, MRI, thermography, infrared
imaging, optical coherence tomography (OCT), photoacoustic imaging, pet imaging, SPECT
imaging, or ultrasound, and the images are placed into a three dimensional coordinate
reference frame 950. The coordinate reference frame 950 refers to the knowledge of
the relationship between anatomic structures, both two dimensional and three dimensional,
the structures placed into a physical coordinate reference. Imaging devices determine
the coordinate frame. Once the coordinate frame is established, the imaging and therapy
transducers 900 can be coupled such that the information from the imaging system is
utilized by the therapeutic transducers to position the energy. Blood vessels may
provide a useful reference frame for deposition of energy as they have a unique imaging
signature. An ultrasound pulse echo can provide a Doppler shift signature to identify
the blood vessel from the surrounding tissue. In an MRI, CT scan, and even an ultrasound
exam, intravenous contrast agents can be utilized to identify flow patterns useful
to determine a coordinate reference for energy deposition. Energy transducers 900
which can deliver ultrasound, light, radiation, ionizing radiation, or microwave energy
are placed in the same three-dimensional reference frame as the renal arteries, at
which time a processor (e.g. using an algorithm) can determine how to direct the transducers
to deliver energy to the region 220 of the nerves 910. The algorithm consists of a
targeting feature (planning feature) which allows for prediction of the position and
energy deposition of the energy leaving the transducers 900.
[0213] Once the three dimensional coordinate reference frames 950 are linked or coupled,
the planning and prediction algorithm can be used to precisely position the energy
beams at a target in the body.
[0214] The original imaging modality can be utilized to locate the renal sympathetic region
can be used to track the motion of the region during treatment. For example, the imaging
technology used at time zero is taken as the baseline scan and subsequent scans at
time t1 are compared to the baseline scan, t0. The frequency of updates can range
from a single scan every few seconds to many scans per second. With ultrasound as
the imaging technology, the location might be updated at a frame rate greater than
50 Hz and up to several hundred Hz or thousand Hz. With MRI as the imaging modality,
the imaging refresh rate might be closer to 30 Hz. In other embodiments, internally
placed fiducials transmit positional information at a high frequency and this information
is utilized to fuse the target with an initial external imaging apparatus. Internal
fiducials might include one or more imageable elements including doppler signals,
regions of blood vessels, ribs, kidneys, and blood vessels and organs other than the
target (e.g. vena cava, adrenal gland, ureter). These fiducials can be used to track
the region being treated and/or to triangulate to the region to be treated.
[0215] In some embodiments (figure 3C), a temporary fiducial 960 is placed in the region,
such as in the artery 965, renal vein 975, aorta 945, and/or vena cava 985; such a
fiducial is easily imageable from outside the patient.
[0216] Figure 3D depicts an imageable transducer 960 in a blood vessel 967 within a coordinate
reference 975 on a monitor system 950. Alternatively, the temporary fiducial 960 is
a transducer which further improves the ability to image and track the region to deliver
therapy. The temporary fiducial might be a mechanical, optical, electromechanical,
a radiofrequency radiotransmitter, global positioning tracking (GPS) device, or ultrasound
responsive technology. Similar devices might be found in patent nos.
6,656,131 and
7,470,241 which are incorporated by reference herein.
[0217] Internal reflections (e.g. speckles) can be tracked as well. These speckles are inherent
characteristics of tissue as imaged with ultrasound. They can be tracked and incorporated
into treatment planning algorithm and then linked to the therapeutic transducers.
[0218] In some embodiments, a test dose of energy can be applied to the renal sympathetic
region and then a test performed to determine if an effect was created. For example,
a small amount of heat or vibratory energy can be delivered to the region of the sympathetic
nerves and then a test of sympathetic activity such as microneurography (detection
of sympathetic nerve activity around muscles and nerves which correlate with the beating
heart) can be performed. Past research and current clinical data have shown that the
sympathetic nerves to the peripheral muscles are affected by interruption of the renal
afferent nerves. The degree of temperature rise with the small degree of heat can
be determined through the use of MRI thermometry or an ultrasound technique and the
temperature rise can be determined or limited to an amount which is reversible.
[0219] In another embodiment, a stimulus is applied to a region such as the skin and an
output downstream from the skin is detected. For example, a vibratory energy might
be applied to the skin and a sympathetic outflow such as the heart rate might be detected.
In another embodiment, heat or cold might be applied to the skin and heart rate, blood
pressure; vasoconstriction might be detected as an output.
[0220] Alternatively, ultrasonic imaging can be utilized to determine the approximate temperature
rise of the tissue region. The speed of ultrasonic waves is dependent on temperature
and therefore the relative speed of the ultrasound transmission from a region being
heated will depend on the temperature, therefore providing measureable variables to
monitor. In some embodiments, microbubbles are utilized to determine the rise in temperature.
Microbubbles expand and then degrade when exposed to increasing temperature so that
they can then predict the temperature of the region being heated. A technique called
ultrasound elastography can also be utilized. In this embodiment, the elastic properties
of tissue are dependent on temperature and therefore the elastography may be utilized
to track features of temperature change. The microbubbles can also be utilized to
augment the therapeutic effect of the region being targeted. For example, the microbubbles
can be utilized to release a pharmaceutical when the ultrasound reaches them. Alternatively,
the microbubble structure can be utilized to enhance imaging of the treatment region
to improve targeting or tracking of the treatment region.
[0221] In some embodiments, only the temperature determination is utilized. That is, the
temperature sensing embodiments and algorithms are utilized with
any procedure in which heating is being performed. For example, in a case where heating
of the renal nerve region is performed using radiofrequency ablation through the renal
artery, imaging of the region from a position external to the patient can be performed
while the renal artery region is being heated via radiofrequency methods. Imaging
can be accomplished utilizing MRI, ultrasound, infrared, or OCT methods.
[0222] In another embodiment, a test may be performed on the baroreceptor complex at the
region of the carotid artery bifurcation. After the test dose of energy is applied
to the renal artery complex, pressure can be applied to the carotid artery complex;
typically, with an intact baroreceptor complex, the systemic blood pressure would
decrease after application of pressure to the carotid artery. However, with renal
afferent nerves which have been inhibited, the baroreceptors will not be sensitive
to changes in blood pressure and therefore the efficacy of the application of the
energy to the renal nerves can be determined. Other tests include attaining indices
of autonomic function such as microneurography, autonomic function variability, etc.
[0223] In another embodiment, stimulation of the baroreceptor complex is accomplished
non-invasively via ultrasound pulses applied externally to the region of the carotid body. The ultrasound
pulses are sufficient to stimulate the sinus to affect a blood pressure change, a
change which will be affected when an afferent nerve such as the renal afferents have
been altered.
[0224] More specifically, this methodology is depicted in Figure 3E. An ultrasound pulse
980 is utilized to stimulate the carotid sinus which will lower blood pressure transiently
982 by activating the baroreceptor complex; activation of the carotid sinus 980 simulates
the effect of an increase in blood pressure which leads to a compensatory outflow
of parasympathetic activity and decreased sympathetic outflow, subsequently lowering
blood pressure. In the instance when the afferent system (e.g. from the kidney) has
been inhibited, the pressure will not be modifiable as quickly if at all. In this
case, stimulating the baroreceptor complex does not result in a lowering of blood
pressure 986, then the treatment was successful. This diagnostic technique can therefore
be utilized to determine the effect of a therapy on a system such as the renal nerve
complex. If therapy is successful, then the modifying effect of the ultrasound pulse
on the carotid sinus and blood pressure is less dramatic and the therapeutic (treatment
of afferent nerves)successful; therefore, therapy can be discontinued 988 temporarily
or permanently. If the blood pressure continues to decrease 982 with the baroreceptor
stimulation, then the therapeutic effect has not been reached with the therapeutic
treatment and it needs to be continued 984 and/or the dose increased. Other methods
to stimulate the baroreceptor complex are to apply pressure in the vicinity with hands,
compression balloons, and the like.
[0225] Other regions of the autonomic nervous system can also be affected directly by the
technology described herein by applying energy from one region and transmitted through
tissue to another region. For example, figure 4a illustrates a system in which energy
external to the internal carotid artery 1020 is applied to a portion of the autonomic
nervous system, the carotid body complex 1000, through the internal jugular vein 1005,
and to the carotid body 1000 and/or vagus nerve 1020 region. Ablative energy, vibratory,
or electrical stimulation energy can be utilized to affect the transmission of signals
to and from these nerves. The transmission in this complex can be augmented, interrupted,
inhibited with over-stimulation, or a combination of these effects via energy (e.g.
ultrasound, electrical stimulation, etc.).
[0226] In addition, or in place of, in other embodiments, energy may be applied to peripheral
nerves typically known as motor nerves but which contain autonomic fibers. Such nerves
include the saphenous nerve, femoral nerves, lumbar nerves, median nerves, ulnar nerves,
and radial nerves. In some embodiments, energy is applied to the nerves and specific
autonomic fibers are affected rather than the other neural fibers (e.g. motor or somatic
sensory fibers or efferent or afferent autonomic nerves). In some embodiments, other
types of autonomic fibers are affected with energy applied internally or externally.
For example, nerves surrounding the superior mesenteric artery, the inferior mesenteric
artery, the femoral artery, the pelvic arteries, etc. can be affected by the energy
in a specific manner so as to create changes in the autonomic responses of the blood
vessels themselves or organs related to the blood vessels, the nerves running through
and along the vessels to the organs.
[0227] In another embodiment, in Figure 4a, a catheter 1010 is advanced into the internal
jugular vein 1005 and when in position, stimulation or ablative energy 1020 is directed
toward the autonomic nerves, e.g. the vagus nerve and the carotid sinus/body 1000,
from the catheter positioned in the venous system 1005.
[0228] In a similar type of embodiment 1100, a catheter based therapeutic energy source
1110 can be inserted into the region of the renal arteries or renal veins (Figure
4B) to stimulate or inhibit the renal nerves from the inside of the vessel, either
the renal artery 1105 or renal vein 1106. Energy is transferred through the vessel
(e.g. renal vein) to reach the nerves around another vessel (e.g. renal artery). For
example, a catheter delivering unfocused ultrasound energy with powers in the range
of 50 mW/cm
2 to 50 kW/cm
2 can be placed into the renal artery and the energy transmitted radially around the
artery or vein to the surrounding nerves. As discussed below, the 500mW - 2500 W/cm
2 is appropriate to create the specific nerve dysfunction to affect the norepinephrine
levels in the kidney, a surrogate of nerve function which has been shown to lead to
decreases in blood pressure over time. Pulsed ultrasound, for example, 100 pulse trains
with each lasting less than 1 second each, can be applied to the region.
[0229] In another embodiment, light is applied through the vessel from within the blood
vessel. Infrared, red, blue, and near infrared can all be utilized to affect the function
of nerves surrounding blood vessels. For example, a light source is introduced into
the renal artery or renal vein 1105, 1106 and the light transmitted to the region
surrounding the blood vessels. In a preferred embodiment, a photosensitizing agent
is utilized to hasten the inhibition or destruction of the nerve bundles with this
technique. Photosensitizing agents can be applied systemically to infiltrate the region
around the blood vessels. Light is then applied from inside the vessel to the region
of the nerves outside the vessel. For example, the light source is placed inside the
renal vein and then light is transmitted through the vein wall to the adventitial
region around the wall activating the photosensitizer and injuring or inhibiting the
nerves in the adventitia through an apoptosis pathway. The light source may provide
light that is visible, or light that is non-visible.
[0230] The therapies in Figs 4a-b can be delivered on an acute basis such as for example
in an ICU or critical care setting. In such a case, the therapy would be acute and
intermittent, with the source outside the patient and the catheter within the patient
as shown in Figures 4a-b. The therapy can be utilized during times of stress for the
patient such that the sympathetic system is slowed down. After the intensive care
admission is nearing a close, the catheter and unit can be removed from the patient.
In one embodiment, a method is described in which a catheter is placed within a patient
to deliver energy to a region of the body sufficient to partially or fully inhibit
an autonomic nerve complex during a state of profound sympathetic activation such
as shock, sepsis, myocardial infarction, pancreatitis, post-surgical. After the acute
phase of implantation during which the sympathetic system is modulated, the device
is removed entirely.
[0231] Figs. 5a-b illustrates the eye in close up detail with sympathetic nerves surrounding
the posterior of the eye. In the eye, glaucoma is a problem of world-wide importance.
The most commonly prescribed medication to treat glaucoma is timoptic, which is a
non-selective β1 and β2 (adrenergic) antagonist. Compliance with this pharmaceutical
is a major problem and limits its effectiveness in preventing the complications of
glaucoma, the major complication being progression of visual dysfunction.
[0232] Ultrasound, or other energy transducers 7000, can be applied to focus energy from
an external region (e.g. a distance from the eye in an external location) anterior
to the eye or to a region posteriorly behind the eye 2500 on the sympathetic 2010
or parasympathetic ganglia, all of which will affect lowering of intra-ocular pressure.
The energy transducers 7000 apply ablative or near ablative energy to the adventitia
of the blood vessels. In some embodiments, the energy is not ablative but vibratory
at frequencies (e.g. 1-5 Mhz) and penetration depths (e.g. 0.5 mm to 0.5 cm) sufficient
to inhibit the function of the nerves which are responsible for intra-ocular pressure.
Lower energy (e.g. sub-ablative) can be applied to the eye to assist in drug delivery
or to stimulate tissue healing type of tissue responses.
[0233] Figure 5b depicts the anatomy of the nerves which travel behind the eye 2500. In
this illustration, a catheter 2000 is tunneled through the vasculature to the region
of the sympathetic nerves surrounding the arteries of the eye 2010 and utilized to
ablate, stun, or otherwise modulate the efferent and/or afferent nerves through the
wall of the vasculature.
[0234] Figure 6 illustrates an overall schematic of the renal artery, renal vein, the collecting
system, and the more distal vessels and collecting system within the renal parenchyma.
The individual nerves of the autonomic nervous system typically follow the body vasculature
and they are shown in close proximity 3000 to the renal artery as the artery enters
the kidney 3100 proper. The hilum of the kidney contains pressure sensors and chemical
sensors which influence the inputs to the efferent sympathetic system via afferent
nerves traveling from the kidney to the central nervous system and then to the efferent
nervous system. Any one or multiple of these structures can influence the function
of the kidney. Ablative or non-ablative energy can be applied to the renal vein, the
renal artery, the aorta, and/or the vena cava, the renal hilum, the renal parenchyma,
the renal medulla, the renal cortex, etc.
[0235] In another embodiment, selective lesions, constrictions or implants 3200 are placed
in the calyces of the kidney to control or impede blood flow to specific regions of
the kidney. Such lesions or implants can be placed on the arterial 3010 or venous
sides 3220 of the kidney. In some embodiments, the lesions/implants are created so
as to selectively block certain portions of the sympathetic nerves within the kidney.
The lesions also may be positioned so as to ablate regions of the kidney which produce
hormones, such as renin, which can be detrimental to a patient in excess. The implants
or constrictions can be placed in the aorta 3210 or the renal vein 3230. The implants
can be active implants, generating stimulating energy chronically or multiple ablative
or inhibitory doses discretely over time.
[0236] In the renal vein 3230, the implants 3220, 3200 might cause an increase in the pressure
within the kidney (by allowing blood flow to back up into the kidney and increase
the pressure) which will prevent the downward spiral of systolic heart failure described
above because the kidney will act as if it is experiencing a high pressure head. That
is, once the pressure in the kidney is restored or artificially elevated by increased
venous pressure, the relative renal hypotension signaling to retain electrolytes and
water will not be present any longer and the kidney will "feel" full and the renal
sympathetic stimulation will be turned off. In one embodiment, a stent which creates
a stenosis is implanted using a catheter delivery system. In another embodiment, a
stricture 3220 is created using heat delivered either externally or internally. Externally
delivered heat is delivered via direct heating via a percutaneous procedure (through
the skin to the region of the kidney) or transmitted through the skin (e.g. with HIFU
focused through the skin). In one embodiment, an implant is placed between girota's
fascia and the cortex of the kidney. The implant can stimulate or inhibit nerves surrounding
the renal blood vessels, or even release pharmaceuticals in a drug delivery system.
[0237] Figure 7a depicts at least partial ablation of the renal sympathetic nerves 4400
to the kidney using an imaging system such as an MRI machine or CT scanner 4000. The
MRI/CT scan can be linked to a focused ultrasound (HIFU) machine to perform the ablations
of the sympathetic nerves 4400 around the region of the renal artery 4500. The MRI/CT
scan performs the imaging 4010 and transmits data (e.g. three dimensional representations
of the regions of interest) to the ultrasound controller which then directs the ultrasound
to target the region of interest with low intensity ultrasound (50-1000mW/cm2), heat
(>1000 mW/cm2), cavitation, or a combination of these modalities and/or including
introduction of enhancing bioactive agent delivery locally or systemically (sonodynamic
therapy). Optionally, a doppler ultrasound or other 3D/4D ultrasound is performed
and the data pushed to the MRI system to assist with localization of the pathology;
alternatively, the ultrasound data are utilized to directly control the direction
of the energy being used to target the physiologic processes and CT/MRI is not obtained.
Using this imaging and ablation system from a position external to a patient, many
regions of the kidney can be treated such as the internal calyces 4350, the cortex
4300, the medulla 4320, the hilum 4330, and the region 4340 close to the aorta.
[0238] Further parameters which can be measured include temperature via thermal spectroscopy
using MRI or ultrasound thermometry/elastography; thermal imaging is a well-known
feature of MRI scanners; the data for thermal spectroscopy exists within the MRI scan
and can be extrapolated from the recorded data in real time by comparing regions of
interest before and after or during treatment. Temperature data overlaid on the MRI
scan enables the operator of the machine to visualize the increase in temperature
and therefore the location of the heating to insure that the correct region has indeed
been ablated and that excessive energy is not applied to the region. Having temperature
data also enables control of the ablation field as far as applying the correct temperature
for ablation to the nerves. For example, the temperature over time can be determined
and fed back to the operator or in an automated system, to the energy delivery device
itself. Furthermore, other spectroscopic parameters can be determined using the MRI
scan such as oxygenation, blood flow, or other physiologic and functional parameters.
In one embodiment, an alternating magnetic field is used to stimulate and then over-stimulate
or inhibit an autonomic nerve (e.g. to or from the kidney).
[0239] Elastography is a technique in which the shear waves of the ultrasound beam and reflectance
are detected. The tissue characteristics change as the tissue is heated and the tissue
properties change. An approximate temperature can be assigned to the tissue based
on elastography and the progress of the heating can be monitored.
[0240] MRI scanners 4000 generally consist of a magnet and an RF coil. The magnet might
be an electromagnet or a permanent magnet. The coil is typically a copper coil which
generates a radiofrequency field. Recently, permanent magnets have been utilized to
create MRI scanners which are able to be used in almost any setting, for example a
private office setting. Office based MRI scanners enable imaging to be performed quickly
in the convenience of a physician's office as well as requiring less magnetic force
(less than 0.5 Tesla) and as a consequence, less shielding. The lower tesla magnets
also provides for special advantages as far as diversity of imaging and resolution
of certain features. Importantly, the permanent magnet MRI scanners are open scanners
and do not encapsulate the patient during the scan.
[0241] In one embodiment, a permanent magnet MRI is utilized to obtain an MRI image of the
region of interest 4010. High intensity focused 4100 ultrasound is used to target
the region of interest 4600 identified using the MRI. In one embodiment, the MRI is
utilized to detect blood flow within one or more blood vessels such as the renal arteries,
renal veins, superior mesenteric artery, veins, carotid arteries and veins, aortic
arch coronary arteries, veins, to name a subset.
[0242] Image 4010 is or can be monitored by a health care professional to ensure that the
region of interest is being treated and the treatment can be stopped if the assumed
region is not being treated. Alternatively, an imaging algorithm can be initiated
in which the region of interest is automatically (e.g. through image processing) identified
and then subsequent images are compared to the initial demarcated region of interest.
[0243] Perhaps, most importantly, with MRI, the region around the renal arteries can be
easily imaged as can any other region such as the eye, brain, prostate, breast, liver,
colon, spleen, aorta, hip, knee, spine, venous tree, and pancreas. The imaging from
the MRI can be utilized to precisely focus the ultrasound beam to the region of interest
around the renal arteries or elsewhere in the body. With MRI, the actual nerves to
be modified or modulated can be directly visualized and targeted with the energy delivered
through the body from the ultrasound transducers. One disadvantage of MRI can be the
frame acquisition (difficulty in tracking the target) rate as well as the cost of
introducing an MRI machine into the treatment paradigm. In these regards, ultrasound
imaging offers a much more practical solution.
[0244] Figure 7d depicts a method of treating a region with high intensity focused ultrasound
(HIFU). Imaging with an MRI 4520 or ultrasound 4510 (or preferably both) is performed.
MRI can be used to directly or indirectly (e.g. using functional MRI or spectroscopy)
to visualize the sympathetic nerves. T1 weighted or T2 weighted images can be obtained
using the MRI scanner. In addition to anatomic imaging, the MRI scanner can also obtain
temperature data regarding the effectiveness of the ablation zone as well as the degree
to which the zone is being heated and which parts of the zones are being heated. Other
spectroscopic parameters can be added as well such as blood flow and even nerve activity.
Ultrasound 4510 can be used to add blood flow to the images using Doppler imaging.
The spectroscopic data can be augmented by imaging moieties such as particles, imaging
agents, or particles coupled to imaging agents which are injected into the patient
intravenously, or locally, and proximal to the region of the renal arteries; these
imaging moieties may be visualized on MRI, ultrasound, or CT scan. Ultrasound can
also be utilized to determine information regarding heating. The reflectance of the
ultrasonic waves changes as the temperature of the tissue changes. By comparing the
initial images with the subsequent images after heating, the temperature change which
occurred after the institution of heating can be determined.
[0245] In one embodiment, the kidneys are detected by a cross-sectional imaging modality
such as MRI, ultrasound, or CT scan. The renal arteries and veins are detected within
the MRI image utilizing contrast or not utilizing contrast. Next, the imaging data
is placed into a three dimensional coordinate system which is linked to one or more
ultrasound (e.g. HIFU) transducers 4540 which focus ultrasound onto the region of
the renal arteries in the coordinate frame 4530. The linking, or coupling, of the
imaging to the therapeutic transducers is accomplished by determining the 3 dimensional
position of the target by creating an anatomic model. The transducers are placed in
a relative three dimensional coordinate frame as well. For example, the transducers
can be placed in the imaging field 4520 during the MRI or CT scan such that the cross-sectional
pictures include the transducers. Optionally, the transducers contain motion sensors,
such as electromagnetic, optical, inertial, MEMS, and accelerometers, one or more
of which allow for the transducer position to be monitored if for example the body
moves relative to the transducer or the operator moves relative to the body. With
the motion sensors, the position of the transducers can be determined with movement
which might occur during the therapy. The updated information can then be fed back
to the ultrasound therapy device so as to readjust the position of the therapy.
[0246] In one embodiment, a system is described in which the blood flow in the renal artery
is detected by detecting the walls of the artery or renal vein or the blood flow in
the renal artery or the renal vein. The coordinate reference of the blood vessels
is then transmitted to the therapeutic transducer, for example, ultrasound. The therapeutic
transducer is directed to the renal blood vessels using the information obtained by
imaging. A model of the vessels indicates the blood flow of the vessels and the walls
of the vessels where the nerves reside. Energy is then applied to the model of the
vessels to treat the nerves around the vessels.
[0247] Alternatively, in another embodiment, ultrasound is utilized and the ultrasound image
4510 can be directly correlated to the origin of the imaging transducer. The therapeutic
transducer 4540 in some embodiments is the same as the imaging transducer and therefore
the therapeutic transducer is by definition coupled in a coordinate reference 4540
once the imaging transducer coordinates are known. If the therapeutic transducer and
the imaging transducer are different devices, then they can be coupled by knowledge
of the relative position of the two devices. The region of interest (ROI) is highlighted
in a software algorithm; for example, the renal arteries, the calyces, the medullary
region, the cortex, the renal hila, the celiac ganglia, the aorta, or any of the veins
of the venous system as well. In another embodiment, the adrenal gland, the vessels
traveling to the adrenal gland, or the autonomic nerves traveling to the adrenal gland
are targeted with focused ultrasound and then either the medulla or the cortex of
the adrenal gland or the nerves and arteries leading to the gland are partially or
fully ablated with ultrasonic energy.
[0248] The targeting region or focus of the ultrasound is the point of maximal intensity.
In some embodiments, targeting focus is placed in the center of the artery such that
the walls on either side receive equivalent amounts of energy or power and can be
heated more evenly than if one wall of the blood vessel is targeted. In some embodiments
in which a blood vessel is targeted, the blood vessel being an artery and the artery
having a closely surrounding vein (e.g. the renal artery/vein pedicle), the center
of the focus might be placed at the boundary of the vein and the artery.
[0249] Once the transducers are energized 4550 after the region is targeted, the tissue
is heated 4560 and a technique such as MRI thermography 4570 or ultrasound thermography
is utilized to determine the tissue temperature. During the assessment of temperature,
the anatomic data from the MRI scan or the Doppler ultrasound is then referenced to
ensure the proper degree of positioning and the degree of energy transduction is again
further assessed by the modeling algorithm 4545 to set the parameters for the energy
transducers 4550. If there is movement of the target, the transducers may have to
be turned off and the patient repositioned. Alternatively, the transducers can be
redirected to a different position within the coordinate reference frame.
[0250] Ablation can also be augmented using agents such as magnetic nanoparticles or liposomal
nanoparticles which are responsive to a radiofrequency field generated by a magnet.
These particles can be selectively heated by the magnetic field. The particles can
also be enhanced such that they will target specific organs and tissues using targeting
moieties such as antibodies, peptides, etc. In addition to the delivery of heat, the
particles can be activated to deliver drugs, bioactive agents, or imaging agents at
the region at which action is desired (e.g. the renal artery). The particles can be
introduced via an intravenous route, a subcutaneous route, a direct injection route
through the blood vessel, or a percutaneous route. As an example, magnetic nanoparticles
or microparticles respond to a magnetic field by generating heat in a local region
around them. Similarly, liposomal particles might have a metallic particle within
such that the magnetic particle heats up the region around the liposome but the liposome
allows accurate targeting and biocompatibility.
[0251] The addition of Doppler ultrasound 4510 may be provided as well. The renal arteries
are (if renal arteries or regions surrounding the arteries are the target) placed
in a 3D coordinate reference frame 4530 using a software algorithm with or without
the help of fiducial markers. Data is supplied to ultrasound transducers 4540 from
a heat modeling algorithm 4545 and the transducers are energized with the appropriate
phase and power to heat the region of the renal artery to between 40° C and 90° C
within a time span of several minutes. The position within the 3D coordinate reference
is also integrated into the treatment algorithm so that the ultrasound transducers
can be moved into the appropriate position. The ultrasound transducers may have frequencies
below 1 megahertz (MHz), from 1-20 MHz, or above 30 Mhz, or around 750 kHz, 500 kHz,
or 250 kHz. The transducers may be in the form of a phased array, either linear or
curved, or the transducers may be mechanically moved so as to focus ultrasound to
the target of interest. In addition, MRI thermography 4570 can be utilized so as to
obtain the actual temperature of the tissue being heated. These data can be further
fed into the system to slow down or speed up the process of ablation 4560 via the
transducers 4550.
[0252] Aside from focused ultrasound, ultrasonic waves can be utilized directly to either
heat an area or to activate pharmaceuticals in the region of interest. There are several
methodologies to enhance drug delivery using focused ultrasound. For example, particles
can release pharmaceutical when they are heated by the magnetic field. Liposomes can
release a payload when they are activated with focused ultrasound. Ultrasound waves
have a natural focusing ability if a transducer is placed in the vicinity of the target
and the target contains an activateable moiety such as a bioactive drug or material
(e.g. a nanoparticle sensitive to acoustic waves). Examples of sonodynamically activated
moieties include some porphyrin derivatives.
[0253] So as to test the region of interest and the potential physiologic effect of ablation
in that region, the region can be partially heated or vibrated with the focused ultrasound
to stun or partially ablate the nerves. Next, a physiologic test such as the testing
of blood pressure or measuring norepinephrine levels in the blood, kidney, blood vessels
leading to or from the kidney, can be performed to ensure that the correct region
was indeed targeted for ablation. Depending on the parameter, additional treatments
may be performed.
[0254] Clinically, this technique might be called fractionation of therapy which underscores
one of the major advantages of the technique to apply external energy versus applying
internal energy to the renal arteries. An internal technique requires invasion through
the skin and entry into the renal artery lumens which is costly and potentially damaging.
Patients will likely not accept multiple treatments, as they are highly invasive and
painful. An external technique allows for a less invasive treatment to be applied
on multiple occasions, made feasible by the low cost and minimal invasion of the technology
described herein.
[0255] In another embodiment, a fiducial is utilized to demarcate the region of interest.
A fiducial can be intrinsic (e.g. part of the anatomy) or the fiducial can be extrinsic
(e.g. placed in position). For example, the fiducial can be an implanted fiducial,
an intrinsic fiducial, or device placed in the blood vessels, or a device placed percutaneously
through a catheterization or other procedure. The fiducial can also be a bone, such
as a rib, or another internal organ, for example, the liver. In one embodiment, the
fiducial is a beacon or balloon or balloon with a beacon which is detectable via ultrasound.
In one embodiment, the blood flow in the renal arteries, detected via Doppler or B-mode
imaging, is the fiducial and its relative direction is determined via Doppler analysis.
Next, the renal arteries, and specifically, the region around the renal arteries are
placed into a three dimensional coordinate frame utilizing the internal fiducials.
A variant of global positioning system technology can be utilized to track the fiducials
within the artery or around the arteries. In this embodiment, a position sensor is
placed in the artery or vein through a puncture in the groin. The position of the
sensor is monitored as the sensor is placed into the blood vessel and its position
in physical space relative to the outside of the patient, relative to the operator
and relative to the therapeutic transducer is therefore known. The three dimensional
coordinate frame is transmitted to the therapeutic ultrasound transducers and then
the transducers and anatomy are coupled to the same coordinate frame. At this point,
the HIFU is delivered from the transducers, calculating the position of the transducers
based on the position of the target in the reference frame.
[0256] In one embodiment, a virtual fiducial is created via an imaging system. For example,
in the case of a blood vessel such as the renal artery, an image of the blood vessel
using B-mode ultrasound can be obtained which correlates to the blood vessel being
viewed in direct cross section (1705; figure 17F). When the vessel is viewed in this
type of view, the center of the vessel can be aligned with the center 1700 of an ultrasound
array (e.g. HIFU array 1600) and the transducers can be focused and applied to the
vessel, applying heat lesions 1680 to regions around the vessel 1705. With different
positions of the transducers 1610 along a circumference or hemisphere 1650, varying
focal points can be created 1620, 1630, 1640. The directionality of the transducers
allows for a lesion(s) 1620,1630,1640 which run lengthwise along the vessel 1700.
Thus, a longitudinal lesion 1620-1640 can be produced along the artery to insure maximal
inhibition of nerve function. In some embodiments, the center of the therapeutic ultrasound
transducer is off center relative to the center of the vessel so that the energy is
applied across the vessel wall at an angle, oblique to the vessel.
[0257] In this method of treatment, an artery such as a renal artery is viewed in cross-section
or close to a cross-section under ultrasound guidance. In this position, the blood
vessel is substantially parallel to the axis of the spherical transducer so as to
facilitate lesion production. The setup of the ultrasound transducers 1600 has previously
been calibrated to create multiple focal lesions 1620, 1630, 1640 along the artery
if the artery is in cross-section 1680.
[0258] In one embodiment, the fiducial is an intravascular fiducial such as a balloon or
a hermetically sealed transmitting device. The balloon is detectable via radiotransmitter
within the balloon which is detectable by the external therapeutic transducers. The
balloon can have three transducers, each capable of relaying its position so that
the balloon can be placed in a three dimensional coordinate reference. Once the balloon
is placed into the same coordinate frame as the external transducers using the transmitting
beacon, the energy transducing devices can deliver energy (e.g. focused ultrasound)
to the blood vessel (e.g. the renal arteries) or the region surrounding the blood
vessels (e.g. the renal nerves). The balloon and transmitters also enable the ability
to definitively track the vasculature in the case of movement (e.g. the renal arteries).
In another embodiment, the balloon measures temperature or is a conduit for coolant
applied during the heating of the artery or nerves. Delivery of therapeutic ultrasound
energy to the tissue inside the body is accomplished via the ultrasound transducers
which are directed to deliver the energy to the target in the coordinate frame.
[0259] Once the target is placed in the coordinate frame and the energy delivery is begun,
it is important to maintain targeting of the position, particularly when the target
is a small region such as the sympathetic nerves. To this end, the position of the
region of ablation is compared to its baseline position, both in a three dimensional
coordinate reference frame. The ongoing positional monitoring and information is fed
into an algorithm which determines the new targeting direction of the energy waves
toward the target. In one embodiment, if the position is too far from the original
position (e.g. the patient moves), then the energy delivery is stopped and the patient
repositioned. If the position is not too far from the original position, then the
energy transducers can be repositioned either mechanically (e.g. through physical
movement) or electrically via phased array (e.g. by changing the relative phase of
the waves emanating from the transducers). In another embodiment, multiple transducers
are placed on the patient in different positions and each is turned on or off to result
in the necessary energy delivery. With a multitude of transducers placed on the patient,
a greater territory can be covered with the therapeutic ultrasound. The therapeutic
positions can also serve as imaging positions for intrinsic and/or extrinsic fiducials.
[0260] In addition to heat delivery, ultrasound can be utilized to deliver cavitating energy
which may enable drug delivery at certain frequencies. Cavitating energy can also
lead to ablation of tissue at the area of the focus. A systemic dose of a drug can
be delivered to the region of interest and the region targeted with the cavitating
or other forms of ultrasonic energy. Other types of therapeutic delivery modalities
include ultrasound sensitive bubbles or radiation sensitive nanoparticles, all of
which enhance the effect of the energy at the target of interest.
[0261] Figure 7E depicts the anatomy of the region 4600, the kidneys 4620, renal arteries
4630, and bony structures 4610,4640 as viewed from behind a human patient. Figure
7E depicts the real world placement of the renal arteries into coordinate frame as
outlined in Figure 7D. Cross sectional CT scans from actual human patients were integrated
to create a three-dimensional representation of the renal artery, kidney, and mid-torso
region. Plane 4623 is a plane parallel to the transverse processes and angle 4607
is the angle one has to look up in order to "see" the renal artery under the rib.
[0262] Figure 7F depicts an image of the region of the renal arteries and kidney 4605 using
ultrasound. The renal hilum containing the arteries and vein 4640 can be visualized
using this imaging modality. This image is typical when looking at the kidney and
renal artery from the direction and angle depicted in Figure 7E. Importantly, at the
angle 4607 in 7E, there is no rib in the ultrasound path and there no other important
structures in the path either.
[0263] An ultrasound imaging trial was then performed to detect the available windows to
deliver therapeutic ultrasound to the region of the renal arteries 4630 from the posterior
region of the patient. It was discovered that the window depicted by arrow 4600 and
depicted by arrow 4605 in the cross-sectional ultrasound image from ultrasound (Figure
7F) provided optimal windows to visualize the anatomy of interest (renal pedicle 4640).
[0264] Figure 7G contains some of the important data from the trial 4700, the data in the
"standard position 4730." These data 4720 can be used to determine the configuration
of the clinical HIFU system to deliver ultrasound to the renal hilum. The renal artery
4635 was determined to be 7-17 cm from the skin in the patients on average. The flank
to posterior approach was noted to be optimum to image the renal artery, typically
through the parenchyma of the kidney as shown in figure 7F 4605. The hilum 4640 of
the kidney is approximately 4-8 cm from the ultrasound transducer and the angle of
approach 4637 (4607 in Figure 7E) relative to an axis defined by the line connecting
the two spinous processes and perpendicular to the spine...is approximately -10 to
-48 degrees. It was also noted that the flank approach through the kidney was the
safest approach in that it represents the smallest chances of applying ultrasound
to other organs such as bowel.
[0265] Upon further experimentation, it was discovered that by positioning the patient in
the prone position (backside up, abdomen down), the structures under study 4750...
that is, the renal arteries 4770 and 4780, the kidney hilum were even closer to the
skin and the respiratory motion of the artery and kidney was markedly decreased. Figure
7H depicts these results 4750,4760 showing the renal artery 4770 at 6-10 cm and the
angle of approach 4790 relative to the spine 4607 shallower at -5 to -20 degrees.
[0266] Therefore, with these clinical data, in one embodiment, a method of treatment 4800
(Figure 7I) of the renal nerves in a patient has been devised: 1) identify the rib
4810 and iliac crest 4840 of a patient on the left and right flank of the patient
4810; 2) identify the left or right sided kidney with ultrasound 4820; 3) identify
the hilum of the kidney and the extent the renal hilum is visible along surface of
patient 4820 using an imaging technology; 4) identify the blood vessels leading to
the kidney from one or more angles, extracting the extent of visibility 4860 along
the surface area of the patient's back; 5) determine the distance to the one or more
of the renal artery, renal vein, kidney, and the renal hilum 4850; 6) optionally,
position patient in the prone position with a substantive positioning device underneath
the back of the patient or overtop the abdomen of the patient 4830, to optimize visibility;
7) optionally determine, through modeling, the required power to obtain a therapeutic
dose at the renal hilum and region around the renal blood vessels; 8) apply therapeutic
energy to renal blood vessels; 9) optionally track the region of the blood vessels
to ensure the continued delivery of energy to the region as planned in the modeling;
10)optionally, turning off delivery of energy in the case the focus of the energy
is outside of the planned region.
[0267] Figure 8A depicts a percutaneous procedure and device 5010 in which the region around
the renal artery 5030 is directly approached through the skin from an external position.
A combination of imaging and application of energy (e.g. ablation) may be performed
to ablate the region around the renal artery to treat hypertension, end stage renal
disease, and heart failure. Probe 5010 is positioned through the skin and in proximity
to the kidney 5030. The probe may include sensors at its tip 5020 which detect heat
or temperature or may enable augmentation of the therapeutic energy delivery. Ablative,
ionizing energy, heat, or light may be applied to the region to inhibit the sympathetic
nerves around the renal artery using the probe 5010. Ultrasound, radiofrequency, microwave,
direct heating elements, and balloons with heat or energy sources may be applied to
the region of the sympathetic nerves. Imaging may be included on the probe or performed
separately while the probe is being applied to the region of the renal blood vessels.
[0268] In one embodiment, the percutaneous procedure in Figure 8A is performed under MRI,
CT, or ultrasound guidance to obtain localization or information about the degree
of heat being applied. In one embodiment, ultrasound is applied but at a sub-ablative
dose. That is, the energy level is enough to damage or inhibit the nerves but the
temperature is such that the nerves are not ablated but paralyzed or partially inhibited
by the energy. A particularly preferred embodiment would be to perform the procedure
under guidance from an MRI scanner because the region being heated can be determined
anatomically in real time as well via temperature maps. As described above, the images
after heating can be compared to those at baseline and the signals are compared at
the different temperatures.
[0269] In one embodiment, selective regions of the kidney are ablated through the percutaneous
access route; for example, regions which secrete hormones which are detrimental to
a patient or to the kidneys or other organs. Using energy applied externally to the
patient through the skin and from different angles affords the ability to target any
region in or on the kidney or along the renal nerves or at the region of the adrenal
gland, aorta, or sympathetic chain. This greater breadth in the number of regions
to be targeted is enabled by the combination of external imaging and external delivery
of the energy from a multitude of angles through the skin of the patient and to the
target. The renal nerves can be targeted at their takeoff from the aorta onto the
renal artery, at their synapses at the celiac ganglia, or at their bifurcation point
along the renal artery.
[0270] In a further embodiment, probe 5010 can be utilized to detect temperature or motion
of the region while the ultrasound transducers are applying the energy to the region.
A motion sensor, position beacon, or accelerometer can be used to provide feedback
for the HIFU transducers. In addition, an optional temperature or imaging modality
may be placed on the probe 5010. The probe 5010 can also be used to locate the position
within the laparoscopic field for the ablations to be performed. The dose delivered
by this probe is approximately In figure 8B, intravascular devices 5050,5055 are depicted
which apply energy to the region around the renal arteries 5065 from within the renal
arteries. The intravascular devices can be utilized to apply radiofrequency, ionizing
radiation, and/or ultrasound (either focused or unfocused) energy to the renal artery
and surrounding regions. MRI or ultrasound or direct thermometry can be further utilized
to detect the region where the heat is being applied while the intravascular catheter
is in place.
[0271] In one embodiment, devices 5050, 5055 (Figure 8B) apply ultrasound energy which inhibits
nerve function not by heating, but by mechanisms such as periodic pressure changes,
radiation pressure, streaming or flow in viscous media, and pressures associated with
cavitation, defined as the formation of holes in liquid media. Heat can selectively
be added to these energies but not to create a temperature which ablates the nerves,
only facilitates the mechanism of vibration and pressure. In this embodiment, the
ultrasound is not focused but radiates outward from the source to essentially create
a cylinder of ultrasonic waves that intersect with the wall of the blood vessel. An
interfacial material between the ultrasound transducer and the wall of the artery
may be provided such that the ultrasound is efficiently transducted through the arterial
wall to the region of the nerves around the artery. In another embodiment, the ultrasound
directly enters the blood and propagates through the ultrasound wall to affect the
nerves. In some embodiments, cooling is provided around the ultrasound catheter which
protects the inside of the vessel yet allows the ultrasound to penetrate through the
wall to the regions outside the artery. A stabilization method for the ultrasound
probe is also included in such a procedure. The stabilization method might include
a stabilizing component added to the probe and may include a range finding element
component of the ultrasound so that the operator knows where the ultrasound energy
is being applied.
[0272] Imaging can be performed externally or internally in this embodiment in which a catheter
is placed inside the renal arteries. For example, external imaging with MRI or Ultrasound
may be utilized to visualize changes during the ultrasound modulation of the nerve
bundles. Indeed, these imaging modalities may be utilized for the application of any
type of energy within the wall of the artery. For example, radiofrequency delivery
of energy through the wall of the renal artery may be monitored through similar techniques.
Thus the monitoring of the procedural success of the technique is independent of the
technique in most cases.
[0273] Alternatively, in another embodiment, the devices 5050, 5055 can be utilized to direct
externally applied energy (e.g. ultrasound) to the correct place around the artery
as the HIFU transducers deliver the energy to the region. For example, the intravascular
probe 5050 can be utilized as a homing beacon for the imaging/therapeutic technology
utilized for the externally delivered HIFU.
[0274] Figure 8C depicts a percutaneous procedure to inhibit the renal sympathetic nerves.
Probe 5010 is utilized to approach the renal hilum 5060 region from posterior and
renal artery 5065. With the data presented below, the probe can be armed with HIFU
to denvervate the region. The data presented below indicates the feasibility of this
approach as far as ultrasound enabling denervation of the vessels quickly and easily.
[0275] In another embodiment, the physiologic process of arterial expansion (aneurysms)
is targeted. In figure 9a, an ultrasound transducer is 6005 is placed near the wall
of an aneurysm 6030. Ultrasonic energy 6015 is applied to the wall 6030 of the aneurysm
to thicken the wall and prevent further expansion of the aneurysm. In some embodiments,
clot within the aneurysm is targeted as well so that the clot is broken up or dissolved
with the ultrasonic energy. Once the wall of the aneurysm is heated with ultrasonic
energy to a temperature of between 40 and 70 degrees, the collagen, elastin, and other
extracellular matrix in the wall will harden as it cools, thereby preventing the wall
from further expansion.
[0276] In another embodiment, a material is placed in the aneurysm sac and the focused or
non-focused ultrasound utilized to harden or otherwise induce the material in the
sac to stick to the aorta or clot in the aneurysm and thus close the aneurysm permanently.
In one embodiment therefore, an ultrasound catheter is placed in an aorta at the region
of an aneurysm wall or close to a material in an aneurysmal wall. The material can
be a man-made material placed by an operator or it can be material such as thrombus
which is in the aneurysm naturally. Ultrasound is applied to the wall, or the material,
resulting in hardening of the wall or of the material, strengthening the aneurysm
wall and preventing expansion. The energy can also be applied from a position external
to the patient or through a percutaneously positioned energy delivering catheter.
[0277] Figure 9b 6000 depicts a clot prevention device 6012 (vena cava filter) within a
blood vessel such as the aorta or vena cava 6010. The ultrasound catheter 6005 is
applied to the clot prevention device (filter) 6012 so as to remove the clot from
the device or to free the device 6012 from the wall of the blood vessel in order to
remove it from the blood vessel 6000.
[0278] Figure 9c depicts a device and method in which the celiac plexus 6020 close to the
aorta 6000 is ablated or partially heated using heat or vibrational energy from an
ultrasonic energy source 6005 which can apply focused or unfocused sound waves 6007
at frequencies ranging from 20 kilohertz to 5 Mhz and at powers ranging from 1 mW
to over 100 kW in a focused or unfocused manner. Full, or partial ablation of the
celiac plexus 6020 can result in a decrease in blood pressure via a similar mechanism
as applying ultrasonic energy to the renal nerves; the ablation catheter is a focused
ultrasound catheter but can also be a direct (unfocused) ultrasonic, a microwave transducer,
or a resistive heating element. Energy can also be delivered from an external position
through the skin to the aorta or celiac plexus region.
[0279] Figure 10 depicts a method 6100 to treat a patient with high intensity or low intensity
focused ultrasound (HIFU or LIFU) 6260. In a first step, a CT and/or MRI scan and/or
thermography and/or ultrasound (1 D,2D,3D) is performed 6110. A fiducial or other
marking on or in the patient 6120 is optionally used to mark and track 6140 the patient.
The fiducial can be an implanted fiducial, a temporary fiducial placed internally
or externally in or on the patient, or a fiducial intrinsic to the patient (e.g. bone,
blood vessel, arterial wall) which can be imaged using the CT/MRI/Ultrasound devices
6110. The fiducial can further be a temporary fiducial such as a catheter temporarily
placed in an artery or vein of a patient or a percutaneously placed catheter. A planning
step 6130 for the HIFU treatment is performed in which baseline readings such as position
of the organ and temperature are determined; a HIFU treatment is then planned using
a model (e.g. finite element model) to predict heat transfer, or pressure to heat
transfer, from the ultrasound transducers 6130. The planning step incorporates the
information on the location of the tissue or target from the imaging devices 6110
and allows placement of the anatomy into a three dimensional coordinate reference
such that modeling 6130 can be performed.
[0280] The planning step 6130 includes determination of the positioning of the ultrasound
transducers as far as position of the focus in the patient. X,Y,Z, and up to three
angular coordinates are used to determine the position of the ultrasonic focus in
the patient based on the cross sectional imaging 6110. The HIFU transducers might
have their own position sensors built in so that the position relative to the target
can be assessed. Alternatively, the HIFU transducers can be rigidly fixed to the table
on which the patient rests so that the coordinates relative to the table and the patient
are easily obtainable. The flow of heat is also modeled in the planning step 6130
so that the temperature at a specific position with the ultrasound can be planned
and predicted. For example, the pressure wave from the transducer is modeled as it
penetrates through the tissue to the target. For the most part, the tissue can be
treated as water with a minimal loss due to interfaces. Modeling data predicts that
this is the case. The relative power and phase of the ultrasonic wave at the target
can be determined by the positional coupling between the probe and target. A convective
heat transfer term is added to model heat transfer due to blood flow, particularly
in the region of an artery. A conductive heat transfer term is also modeled in the
equation for heat flow and temperature.
[0281] Another variable which is considered in the planning step is the size of the lesion
and the error in its position. In the ablation of small regions such as nerves surrounding
blood vessels, the temperature of the regions may need to be increased to a temperature
of 60-90 degrees Celsius to permanently ablate nerves in the region. Temperatures
of 40-60 degrees may temporarily inhibit or block the nerves in these regions and
these temperatures can be used to determine that a patient will respond to a specific
treatment without permanently ablating the nerve region. Subsequently, additional
therapy can be applied at a later time so as to complete the job or perhaps, re-inhibit
the nerve regions.
[0282] An error analysis is also performed during the treatment contemplated in Figure 10.
Each element of temperature and position contains an error variable which propagates
through the equation of the treatment. The errors are modeled to obtain a virtual
representation of the temperature mapped to position. This map is correlated to the
position of the ultrasound transducers in the treatment of the region of interest.
[0283] During the delivery of the treatment 6260, the patient may move, in which case the
fiducials 6120 track the movement and the position of the treatment zone is re-analyzed
6150 and the treatment is restarted or the transducers are moved either mechanically
or electrically to a new focus position.
[0284] In another embodiment, a cross-sectional technique of imaging is used in combination
with a modality such as ultrasound to create a fusion type of image. The cross-sectional
imaging is utilized to create a three dimensional data set of the anatomy. The ultrasound,
providing two dimensional images, is linked to the three dimensional imaging provided
by the cross-sectional machine through fiducial matches between the ultrasound and
the MRI. As a body portion moves within the ultrasound field, the corresponding data
is determined (coupled to) the cross-sectional (e.g. MRI image) and a viewing station
can show the movement in the three dimensional dataset. The ultrasound provides real
time images and the coupling to the MRI or other cross-sectional image depicts the
ultrasound determined position in the three dimensional space.
[0285] Figure 11 depicts the treatment 7410 of another disease in the body of a patient,
this time in the head of a patient. Subdural and epidural hematomas occur as a result
of bleeding of blood vessels in the dural or epidural spaces of the brain, spinal
column, and scalp. Figure 11 depicts a CT or MRI scanner 7300 and a patient 7400 therein.
An image is obtained of the brain 7000 using a CT or MRI scan. The image is utilized
to couple the treatment zone 7100 to the ultrasound array utilized to heat the region.
In one embodiment 7100, a subdural hematoma, either acute or chronic, is treated.
In another embodiment 7200, an epidural hematoma is treated. In both embodiments,
the region of leaking capillaries and blood vessels are heated to stop the bleeding,
or in the case of a chronic subdural hematoma, the oozing of the inflammatory capillaries.
[0286] In an exemplary embodiment of modulating physiologic processes, a patient 7400 with
a subdural or epidural hematoma is chosen for treatment and a CT scan or MRI 7300
is obtained of the treatment region. Treatment planning ensues and the chronic region
of the epidural 7200 or sub-dural 7010 hematoma is targeted for treatment with the
focused ultrasound 7100 transducer technology. Next the target of interest is placed
in a coordinate reference frame as are the ultrasound transducers. Therapy 7100 ensues
once the two are coupled together. The focused ultrasound heats the region of the
hematoma to dissolve the clot and/or stop the leakage from the capillaries which lead
to the accumulation of fluid around the brain 7420. The technology can be used in
place of or in addition to a burr hole, which is a hole placed through the scalp to
evacuate the fluid.
[0287] Figure 12 depicts a laparoscopic based approach 8000 to the renal artery region in
which the sympathetic nerves 8210 can be ligated, interrupted, or otherwise modulated.
In laparoscopy, the abdomen of a patient is insufflated and laparoscopic instruments
introduced into the insufflated abdomen. The retroperitoneum is easily accessible
through a flank approach or (less so) through a transabdominal (peritoneal) approach.
A laparoscopic instrument 8200 with a distal tip 8220 can apply heat or another form
of energy or deliver a drug to the region of the sympathetic nerves 8210. The laparoscopic
instrument can also be utilized to ablate or alter the region of the celiac plexus
8300 and surrounding ganglia. The laparoscope can have an ultrasound transducer 8220
attached, a temperature probe attached, a microwave transducer attached, or a radiofrequency
transducer attached. The laparoscope can be utilized to directly ablate or stun the
nerves(e.g. with a lower frequency/energy) surrounding vessels or can be used to ablate
or stun nerve ganglia which travel with the blood vessels. Similar types of modeling
and imaging can be utilized with the percutaneous approach as with the external approach
to the renal nerves. With the discovery through animal experimentation (see below)
that a wide area of nerve inhibition can be affected with a single ultrasound probe
in a single direction (see above), the nerve region does not have to be directly contacted
with the probe, the probe instead can be directed in the general direction of the
nerve regions and the ultrasound delivered. For example, the probe can be placed on
one side of the vessel and activated to deliver focused or semi-focused ultrasound
over a generalized region which might not contain greater than 1 cm of longitudinal
length of the artery but its effect is enough to completely inhibit nerve function
along.
[0288] Figure 13 depicts an algorithm 8400 for the treatment of a region of interest using
directed energy from a distance. MRI and/or CT with or without an imaging agent 8410
can be utilized to demarcate the region of interest (for example, the ablation zone)
and then ablation 8420 can be performed around the zone identified by the agent using
any of the modalities above. This algorithm is applicable to any of the therapeutic
modalities described above including external HIFU, laparoscopic instruments, intravascular
catheters, percutaneous catheters and instruments, as well as any of the treatment
regions including the renal nerves, the eye, the kidneys, the aorta, or any of the
other nerves surrounding peripheral arteries or veins. Imaging 8430 with CT, MRI,
ultrasound, or PET can be utilized in real time to visualize the region being ablated.
At such time when destruction of the lesion is complete 8440, imaging with an imaging
(for example, a molecular imaging agent or a contrast agent such as gadolinium) agent
8410 can be performed again. The extent of ablation can also be monitored by monitoring
the temperature or the appearance of the ablated zone under an imaging modality. Once
lesion destruction is complete 8440, the procedure is finished. In some embodiments,
ultrasonic diagnostic techniques such as elastography are utilized to determine the
progress toward heating or ablation of a region.
[0289] Figure 14 depicts ablation in which specific nerve fibers of a nerve are targeted
using different temperature gradients, power gradients, or temperatures 8500. For
example, if temperature is determined by MRI thermometry or with another technique
such as ultrasound, infrared thermography, or a thermocouple, then the temperature
can be kept at a temperature in which only certain nerve fibers are targeted for destruction
or inhibition. Alternatively, part or all of the nerve can be turned off temporarily
to then test the downstream effect of the nerve being turned off. For example, the
sympathetic nerves around the renal artery can be turned off with a small amount of
heat or other energy (e.g. vibrational energy) and then the effect can be determined.
For example, norepinephrine levels in the systemic blood, kidney, or renal vein can
be assayed; alternatively, the stimulation
effect of the nerves can be tested after temporary cessation of activity (e.g. skin reactivity,
blood pressure lability, cardiac activity, pulmonary activity, renal artery constriction
in response to renal nerve stimulation). For example, in one embodiment, the sympathetic
activity within a peripheral nerve is monitored; sympathetic activity typically manifests
as spikes within a peripheral nerve electrical recording. The number of spike correlates
with the degree of sympathetic activity or over-activity. When the activity is decreased
by (e.g. renal artery de-inervation), the concentration of spikes in the peripheral
nerve train is decreased, indicating a successful therapy of the sympathetic or autonomic
nervous system. Varying frequencies of vibration can be utilized to inhibit specific
nerve fibers versus others. For example, in some embodiments, the efferent nerve fibers
are inhibited and in other embodiments, the afferent nerve fibers are inhibited. In
some embodiments, both types of nerve fibers are inhibited, temporarily or permanently.
In some embodiments, the C fibers 8520 are selectively blocked at lower heat levels
than the A nerve fibers. In other embodiment, the B fibers are selectively treated
or blocked and in some embodiments, the A fibers 8530 are preferentially blocked.
In some embodiments, all fibers are inhibited by suturing the nerve with a high dose
of ultrasound 8510. Based on the experimentation described above, the power density
to achieve full blockage might be around 100-800 W/cm
2 or with some nerves from about 500 to 2500 W/cm
2. In some embodiments, a pulse train of 100 or more pulses each lasting 1-2 seconds
(for example) and delivering powers from about 50 w/cm
2 to 500 W/cm
2. Indeed, prior literature has shown that energies at or about 100W/Cm
2 is adequate to destroy or at least inhibit nerve function (
Lele, PP. Effects of Focused Ultrasound Radiation on Peripheral Nerve, with Observations
on Local Heating. Experimental Neurology 8, 47-831963 incorporated by reference).
[0290] Figure 15a depicts treatment 8600 of a vertebral body or intervertebral disk 8610
in which nerves within 8640 or around the vertebral column 8630 are targeted with
energy 8625 waves. In one embodiment, nerves around the facet joints are targeted.
In another embodiment, nerves leading to the disks or vertebral endplates are targeted.
In another embodiment, nerves within the vertebral bone 8630 are targeted by heating
the bone itself. Sensory nerves run through canals 8635 in the vertebral bone 8630
and can be inhibited or ablated by heating the bone 8630.
[0291] Figure 15B depicts a close-up of the region of the facet joint. Focused ultrasound
to this region can inhibit nerves involved in back pain which originate at the dorsal
root nerve and travel to the facet joint 8645. Ablation or inhibition of these nerves
can limit or even cure back pain due to facet joint arthropathy. Focused ultrasound
can be applied to the region of the facet joint from a position outside the patient
to the facet joint using powers of between 100 W/cm
2 and 2500 W/cm
2 at the nerve from times ranging from 1 second to 10 minutes.
[0292] Figure 16A depicts a set of lesion types, sizes, and anatomies 8710a-f which lead
to de-innervation of the different portions of the sympathetic nerve tree around the
renal artery. For example, the lesions can be annular, cigar shaped, linear, doughnut
and/or spherical; the lesions can be placed around the renal arteries 8705, inside
the kidney 8710, and/or around the aorta 8700. For example, the renal arterial tree
comprises a portion of the aorta 8700, the renal arteries 8705, and kidneys 8715.
Lesions 8714 and 8716 are different types of lesions which are created around the
aorta 8700 and vascular tree of the kidneys. Lesions 8712 and 8718 are applied to
the pole branches from the renal artery leading to the kidney and inhibit nerve functioning
at branches from the main renal artery. These lesions also can be applied from a position
external to the patient. Lesions can be placed in a spiral shape 8707 along the length
of the artery as well. These lesions can be produced using energy delivered from outside
the blood vessels using a completely non-invasive approach in which the ultrasound
is applied through the skin to the vessel region or the energy can be delivered via
percutaneous approach. Either delivery method can be accomplished through the posterior
approach to the blood vessels as discovered and described above.
[0293] In one method therefore, ultrasound energy can be applied to the blood vessel leading
to a kidney in a pattern such that a circular pattern of heat and ultrasound is applied
to the vessel. The energy is transmitted through the skin in one embodiment or through
the artery in another embodiment. As described below, ultrasound is transmitted from
a distance and is inherently easier to apply in a circular pattern because it doesn't
only rely on conduction.
[0294] Previously, it was unknown and undiscovered whether or not the annular shaped lesions
as shown in figure 16a would have been sufficient to block nerve function of the autonomic
nerves around the blood vessels. Applicant of the subject application discovered that
the annular shaped ablations 8710 not only block function but indeed completely block
nerve function around the renal artery and kidney and with very minimal damage (Figure
16C), if any, to the arteries and veins themselves. In these experiments, focused
ultrasound was used to block the nerves; the ultrasound was transmitted through and
around the vessel from the top (that is, only one side of the vessel) at levels of
200-2500 W/cm
2. Simulations are shown in figure 16B and described below. Norepinephrine levels in
the kidney 8780, which are utilized to determine the degree of nerve inhibition, were
determined before and after application of energy. The lower the levels of norepinephrine,
the more nerves which have been inhibited. In these experiments which were performed,
the norepinephrine levels approached zero 8782 versus controls 8784 which remained
high. In fact, the levels were equal to or lower than the surgically denuded blood
vessels (surgical denudement involves directly cutting the nerves surgically). It
is important that the renal artery and vein walls were remained substantially unharmed;
this is likely due to the fact that the quick arterial blood flow removes heat from
the vessel wall and the fact that the main renal artery is extremely resilient due
to its large size, high blood flow, and thick wall. To summarize, ultrasound (focused
and relatively unfocused) was applied to one side of the renal artery and vein complex.
The marker of nerve inhibition, norepinephrine levels inside the kidney, were determined
to be approaching zero after application to the nerves from a
single direction, transmitting the energy through the artery wall to reach nerves around
the circumference of the artery. The level of zero norepinephrine 8782 indicates essentially
complete abolition of nerve function proving that the annular lesions were in fact
created as depicted in figure 16A and simulated in Figure 16B. Histological results
also confirm the annular nature of the lesions and limited collateral damage as predicted
by the modeling in 16B.
[0295] Therefore, in one embodiment, the ultrasound is applied from a position external
to the artery in such a manner so as to create an annular or semi-annular rim of heat
all the way around the artery to inhibit, ablate, or partially ablate the autonomic
nerves surrounding the artery. The walls or the blood flow of the artery can be utilized
to target the ultrasound to the nerves which, if not directly visualized, are visualized
by use of a model to approximate the position of the nerves based on the position
of the blood vessel.
[0296] Figure 16B further supports the physics and physiology described herein, depicting
a theoretical simulation 8750 of the physical and animal experimentation described
above. That is, focused ultrasound was targeted to a blood vessel in a computer simulation
8750. The renal artery 8755 is depicted within the heating zone generated within a
focused ultrasound field. Depicted is the temperature at <1s 8760 and at approximately
5s 8765 and longer time > 10s 8767. Flow direction 8770 is shown as well. The larger
ovals depict higher temperatures with the central temperature >100°C. The ultrasound
field is transmitted
through the artery 8755, with heat building up around the artery as shown via the temperature
maps 8765. Importantly, this theoretical simulation also reveals the ability of the
ultrasound to travel through the artery and affect both walls of the blood vessel.
These data are consistent with the animal experimentation described above, creating
a unified physical and experimental dataset.
[0297] Therefore, based on the animal and theoretical experimentation, there is proven feasibility
of utilizing ultrasound to quickly and efficiently inhibit the nerves around the renal
arteries from a position external to the blood vessels as well as from a position
external to the skin of the patient.
[0298] Utilizing the experimental simulations and animal experimentation described above,
a clinical device can and has been devised and tested in human patients. Figure 17A
depicts a multi-transducer HIFU device 1100 which applies a finite lesion 1150 along
an artery 1140 (e.g. a renal artery) leading to a kidney 1130. The lesion can be spherical
in shape, cigar shaped 1150, annular shaped 8710 (Figure 16A), or point shaped; however,
in a preferred embodiment, the lesion runs along the length of the artery and has
a cigar shaped 1150. This lesion is generated by a spherical or semi-spherical type
of ultrasound array in a preferred embodiment. Multiple cigar shaped lesion as shown
in Figure 17C leads to a ring type of lesion 1350.
[0299] Figure 17B depicts an imaging apparatus display which monitors treatment. Lesion
1150 is depicted on the imaging apparatus as is the aorta 1160 and renal artery 1155.
The image might depict heat, tissue elastography, vibrations, or might be based on
a simulation of the position of the lesion 1150. Figure 17C depicts another view of
the treatment monitoring, with the renal artery in cross section 1340. Lesion 1350
is depicted in cross section in this image as well. The lesion 1350 might be considered
to circumscribe the vessel 1340 in embodiments where multiple lesions are applied.
[0300] Figure 17D depicts a methodology 1500 to analyze and follow the delivery of therapeutic
focused ultrasound to an arterial region. A key step is to first position 1510 the
patient optimally to image the treatment region; the imaging of the patient might
involve the use of Doppler imaging, M mode imaging, A scan imaging, or even MRI or
CT scan. The imaging unit is utilized to obtain coordinate data 1530 from the doppler
shift pattern of the artery. Next, the focused ultrasound probe is positioned 1520
relative to the imaged treatment region 1510 and treatment can be planned or applied.
[0301] Figure 17E depicts the pathway of the acoustic waves from a spherical or cylindrical
type of ultrasound array 1600. In some embodiments, the transducer is aspherical such
that a sharp focus does not exist but rather the focus is more diffuse in nature or
off the central axis. Alternatively, the asphericity might allow for different pathlengths
along the axis of the focusing. For example, one edge of the ultrasound transducer
might be called upon for 15 cm of propagation while another edge of the transducer
might be called upon to propagate only 10 cm, in which case a combination of difference
frequencies or angles might be required.
[0302] Ultrasound transducers 1610 are aligned along the edge of a cylinder 1650, aimed
so that they intersect at one or more focal spots 1620, 1630,1640 around the vessel
(e.g. renal artery). The transducers 1610 are positioned along the cylinder or sphere
or spherical approximation (e.g. aspherical) 1650 such that several of the transducers
are closer to one focus or the other such that a range of distances 1620, 1630, 1640
to the artery is created. The patient and artery are positioned such that their centers
1700 co-localize with the center of the ultrasound array 1600. Once the centers are
co-localized, the HIFU energy can be activated to create lesions along the length
of the artery wall 1640, 1620, 1630 at different depths and positions around the artery.
The natural focusing of the transducers positioned along a cylinder as in figure 17E
is a lengthwise lesion, longer than in thickness or height, which will run along the
length of an artery 1155 when the artery 1340 is placed along the center axis of the
cylinder. When viewed along a cross section (Figure 17F), the nerve ablations are
positioned along a clock face 1680 around the blood vessel.
[0303] In another embodiment, a movement system for the transducers is utilized so that
the transducers move along the rim of the sphere or cylinder to which they are attached.
The transducers can be moved automatically or semi-automatically, based on imaging
or based on external position markers. The transducers are independently controlled
electrically but coupled mechanically through the rigid structure.
[0304] Importantly, during treatment, a treatment workstation 1300 (Figure 17C) gives multiple
views of the treatment zone with both physical appearance and anatomy 1350. Physical
modeling is performed in order to predict lesion depth and the time to produce the
lesion; this information is fed back to the ultrasound transducers 1100. The position
of the lesion is also constantly monitored in a three dimensional coordinate frame
and the transducer focus at lesions center 1150 in the context of monitoring 1300
continually updated.
[0305] In some embodiments, motion tracking prevents the lesion or patient from moving too
far out of the treatment zone during the ablation. If the patient does move outside
the treatment zone during the therapy, then the therapy can be stopped. Motion tracking
can be performed using the ultrasound transducers, tracking frames and position or
with transducers from multiple angles, creating a three dimensional image with the
transducers. Alternatively, a video imaging system can be used to track patient movements,
as can a series of accelerometers positioned on the patient which indicate movement.
[0306] Figure 18 depicts a micro-catheter 8810 which can be placed into renal calyces 8820;
this catheter allows the operator to specifically ablate or stimulate 8830 regions
of the kidney 8800. The catheter can be used to further allow for targeting of the
region around the renal arteries and kidneys by providing additional imaging capability
or by assisting in movement tracking or reflection of the ultrasound waves to create
or position the lesion. The catheter or device at or near the end of the catheter
may transmit signals outside the patient to direct an energy delivery device which
delivers energy through the skin. Signaling outside the patient may comprise energies
such as radiofrequency transmission outside the patient or radiofrequency from outside
to the inside to target the region surrounding the catheter. The following patent
and patent applications describe the delivery of ultrasound using a targeting catheter
within a blood vessel, and are expressly incorporated by reference herein:
11/583569, 12/762938, 11/583656, 12/247969, 10/633726, 09/721526, 10/780405, 09/747310, 12/202195, 11/619996,09/696076
[0307] In one system 8800, a micro catheter 8810 is delivered to the renal arteries and
into the branches of the renal arteries in the kidney 8820. A signal is generated
from the catheter into the kidney and out of the patient to an energy delivery system.
Based on the generated signal, the position of the catheter in a three dimensional
coordinate reference is determined and the energy source is activated to deliver energy
8830 to the region indicated by the microcatheter 8810.
[0308] In an additional embodiment, station keeping is utilized. Station keeping enables
the operator to maintain the position of the external energy delivery device with
respect to the movement of the operator or movement of the patient. As an example,
targeting can be achieved with the energy delivery system and The microcatheter may
be also be utilized to place a flow restrictor inside the kidney (e.g. inside a renal
vein) to "trick" the kidney into thinking its internal pressure is higher than it
might be. In this embodiment, the kidney generates signals to the central nervous
system to lower sympathetic output to target organs in an attempt to decrease its
perfusion pressure.
[0309] Alternatively, specific regions of the kidney might be responsible for hormone excretion
or other factors which lead to hypertension or other detrimental effects to the cardiovascular
system. The microcatheter can generate ultrasound, radiofrequency, microwave, or X-ray
energy. The microcatheter can be utilized to ablate regions in the renal vein or intra-parenchymal
venous portion as well. In some embodiments, ablation is not required but vibratory
energy emanating from the probe is utilized to affect, on a permanent or temporary
basis, the mechanoreceptors or chemoreceptors in the location of the hilum of the
kidney.
[0310] Figure 19A depicts the application 8900 of energy to the region of the renal artery
8910 and kidney 8920 using physically separated transducers 8930, 8931. Although two
are shown, the transducer can be a single transducer which is connected all along.
The transducer(s) can be spherical or aspherical, they can be couple to an imaging
transducer directly or indirectly where the imaging unit might be separated at a distance.
In contrast to the delivery method of figure 17, figure 19A depicts delivery of ultrasound
transverse to the renal arteries and not longitudinal to the artery. The direction
of energy delivery is the posterior of the patient because the renal artery is the
first vessel "seen" when traveling from the skin toward the anterior direction facilitating
delivery of the therapy. In one embodiment, the transducers 8930,8931 are placed under,
or inferior to the rib of the patient or between the ribs of a patient; next, the
transducers apply an ultrasound wave propagating forward toward the anterior abdominal
wall and image the region of the renal arteries and renal veins, separating them from
one another. In some embodiments, such delivery might be advantageous, if for example,
a longitudinal view of the artery is unobtainable or a faster treatment paradigm is
desirable. The transducers 8930,8931 communicate with one another and are connected
to a computer model of the region of interest being imaged (ROI), the ROI based on
an MRI scan performed just prior to the start of the procedure and throughout the
procedure. Importantly, the transducers are placed posterior in the cross section
of the patient, an area with more direct access to the kidney region. The angle between
the imaging transducers can be as low as 3 degrees or as great as 180 degrees depending
on the optimal position in the patient.
[0311] In another embodiment, an MRI is not performed but ultrasound is utilized to obtain
all or part of the cross-sectional view in Figure 19A. For example, 8930 might contain
an imaging transducer as well as a therapeutic energy source (e.g. ionizing energy,
HIFU, low energy focused ultrasound, etc.)
[0312] Figure 19B depicts an ultrasound image from a patient illustrating imaging of the
region with patient properly positioned as described below. It is this cross section
that can be treated with image guided HIFU of the renal hilum region. The kidney 8935
is visualized in cross section and ultrasound then travels through to the renal artery
8937 and vein 8941. The distance can be accurately measure 8943 with ultrasound (in
this case 8 cm 8943). This information is useful to help model the delivery of energy
to the renal blood vessels.
[0313] Figure 20 depicts an alternative method, system 9000 and device to ablate the renal
nerves 9015 or the nerves leading to the renal nerves at the aorta-renal artery ostium
9010. The intravascular device 9020 is placed into the aorta 9050 and advanced to
the region of the renal arteries 9025. Energy is applied from the transducer 9020
and focused 9040(in the case of HIFU, LIFU, ionizing radiation) to the region of the
takeoff of the renal arteries 9025 from the aorta 9050. This intravascular 9030 procedure
can be guided using MRI and/or MRI thermometry or it can be guided using fluoroscopy,
ultrasound, or MRI. Because the aorta is larger than the renal arteries, the HIFU
catheter can be placed into the aorta directly and cooling catheters can be included
as well. In addition, in other embodiments, non-focused ultrasound can be applied
to the region around the renal ostium or higher in the aorta. Non-focused ultrasound
in some embodiments may require cooling of the tissues surrounding the probe using
one or more coolants but in some embodiments, the blood of the aorta will take the
place of the coolant, by its high flow rate; HIFU, or focused ultrasound, may not
need the cooling because the waves are by definition focused from different angles
to the region around the aorta. The vena cava and renal veins can also be used as
a conduit for the focused ultrasound transducer to deliver energy to the region as
well. In one embodiment, the vena cava is accessed and vibratory energy is passed
through the walls of the vena cava and renal vein to the renal arteries, around which
the nerves to the kidney travel. The veins, having thinner walls, allow energy to
pass through more readily.
[0314] Figure 21a-b depicts an eyeball 9100. Also depicted are the zonules of the eye 9130
(the muscles which control lens shape) and ultrasound transducer 9120. The transducer
9120 applies focused ultrasound energy to the region surrounding the zonules, or the
zonules themselves, in order to tighten them such that a presbyopic patient can accommodate
and visualize object up close. Similarly, heat or vibration applied to the ciliary
muscles, which then increases the outflow of aqueous humor at the region of interest
so that the pressure within the eye cannot build up to a high level. The ultrasound
transducer 9120 can also be utilized to deliver drug therapy to the region of the
lens 9150, ciliary body, zonules, intra-vitreal cavity, anterior cavity 9140, posterior
cavity, etc.
[0315] In some embodiments (Fig. 21b), multiple transducers 9160 are utilized to treat tissues
deep within the eye; the ultrasonic transducers 9170 are focused on the particular
region of the eye from multiple directions so that tissues along the path of the ultrasound
are not damaged by the ultrasound and the focus region and region of effect 9180 is
the position where the waves meet in the eye. In one embodiment, the transducers are
directed through the pars plana region of the eye to target the macula 9180 at the
posterior pole 9175 of the eye. This configuration might allow for heat, vibratory
stimulation, drug delivery, gene delivery, augmentation of laser or ionizing radiation
therapy, etc. In certain embodiments, focused ultrasound is not required and generic
vibratory waves are transmitted through the eye at frequencies from 20 kHz to 10 MHz.
Such energy may be utilized to break up clots in, for example, retinal venous or arterial
occlusions which are creating ischemia in the retina. This energy can be utilized
in combination with drugs utilized specifically for breaking up clots in the veins
of the retina.
[0316] Figure 22 depicts a peripheral joint 9200 being treated with heat and/or vibrational
energy. Ultrasound transducer 9210 emits waves toward the knee joint to block nerves
9260 just underneath the bone periostium 92209250 or underneath the cartilage. Although
a knee joint is depicted, it should be understood that many joints can be treated
including small joints in the hand, intervertebral joints, the hip, the ankle, the
wrist, and the shoulder. Unfocused or focused ultrasonic energy can be applied to
the joint region to inhibit nerve function reversibly or irreversibly. Such inhibition
of nerve function can be utilized to treat arthritis, post-operative pain, tendonitis,
tumor pain, etc. In one preferred embodiment, vibratory energy can be utilized rather
than heat. Vibratory energy applied to the joint nerves can inhibit their functioning
such that the pain fibers are inhibited.
[0317] Figure 23a-b depicts closure of a fallopian tube 9300 of a uterus 9320 using externally
applied ultrasound 9310 so as to prevent pregnancy. MRI or preferably ultrasound can
be utilized for the imaging modality.
[0318] Thermometry can be utilized as well so as to see the true ablation zone in real time.
The fallopian tube 9300 can be visualized using ultrasound, MRI, CT scan or a laparoscope.
Once the fallopian tube is targeted, external energy 9310, for example, ultrasound,
can be utilized to close the fallopian tube to prevent pregnancy. When heat is applied
to the fallopian tube, the collagen in the walls are heated and will swell, the walls
then contacting one another and closing the fallopian preventing full ovulation and
therefore preventing pregnancy. Although there is no doppler signal in the fallopian
tube, the technology for visualization and treatment is similar to that for an artery
or other duct. That is, the walls of the tube are identified and modeled, then focused
ultrasound is applied through the skin to the fallopian tube to apply heat to the
walls of the lumen of the fallopian tube.
[0319] In Figure 23b, a method is depicted in which the fallopian tubes are visualized 9340
using MRI, CT, or ultrasound. HIFU 9350 is applied under visualization with MRI or
ultrasound. As the fallopian tubes are heated, the collagen in the wall is heated
until the walls of the fallopian tube close off. At this point the patient is sterilized
9360. During the treating time, it may be required to determine how effective the
heating is progressing. If additional heat is required, then additional HIFU may be
added to the fallopian tubes until there is closure of the tube and the patient is
sterilized 9360. Such is one of the advantages of the external approach in which multiple
treatments can be applied to the patient, each treatment closing the fallopian tubes
further, the degree of success then assessed after each treatment. A further treatment
can then be applied 9370.
[0320] In other embodiments, ultrasound is applied to the uterus or fallopian tubes to aid
in pregnancy by improving the receptivity of the sperm and/or egg for one another.
This augmentation of conception can be applied to the sperm and egg outside of the
womb as well, for example, in a test tube in the case of extra-uterine fertilization.
[0321] Figure 24 depicts a feedback algorithm to treat the nerves of the autonomic nervous
system. It is important that there be an assessment of the response to the treatment
afterward. Therefore, in a first step, modulation of the renal nerves 9400 is accomplished
by any or several of the embodiments discussed above. An assessment 9410 then ensues,
the assessment determining the degree of treatment effect engendered; if a complete
or satisfactory response is determined 9420, then treatment is completed. For example,
the assessment 9410 might include determination through microneurography, assessment
of the carotid sinus reactivity (described above), heart rate variability, measurement
of norepinephrine levels, etc. With a satisfactory autonomic response, further treatment
might not ensue or depending on the degree of response, additional treatments of the
nerves 9430 may ensue.
[0322] Figure 25 depicts a reconstruction of a patient from CT scan images showing the position
of the kidneys 9520 looking through the skin of a patient 9500. The ribs 9510 partially
cover the kidney but do reveal a window at the inferior pole 9530 of the kidney 9520.
Analysis of many of these reconstructions has lead to clinical paradigm in which the
ribs 9510, pelvis 9420, and the vertebra 9440 are identified on a patient, the kidneys
are identified via ultrasound and then renal arteries are identified via Doppler ultrasound.
[0323] As shown in figure 26a, once the ribs and vertebra are identified with the Doppler
ultrasound, an external energy source 9600 can be applied to the region. Specifically,
focused ultrasound (HIFU or LIFU) can be applied to the region once these structures
are identified and a lesion applied to the blood vessels (renal artery and renal nerve)
9620 leading to the kidney 9610. As described herein, the position of the ultrasound
transducer 9600 is optimized on the posterior of the patient as shown in Figure 26A.
That is, with the vertebra, the ribs, and the iliac crest bordering the region where
ultrasound is applied.
[0324] Based on the data above and specifically the CT scan anatomic information in figure
26A, figure 26B depicts a device and system 9650 designed for treatment of this region
(blood vessels in the hilum of the kidney) in a patient. It contains a 0.5-3 Mhz ultrasound
imaging transducer 9675 in its center and a cutout or attachment location of the ultrasound
ceramic (e.g. PZT) for the diagnostic ultrasound placement. It also contains a movement
mechanism 9660 to control the therapeutic transducer 9670. The diagnostic ultrasound
device 9675 is coupled to the therapeutic device in a well-defined, known relationship.
The relationship can be defined through rigid or semi-rigid coupling or it can be
defined by electrical coupling such as through infrared, optical-mechanical coupling
and/or electro-mechanical coupling. Along the edges of the outer rim of the device,
smaller transducers 9670 can be placed which roughly identify tissues through which
the ultrasound travels. For example, simple and inexpensive one or two-dimensional
transducers might be used so as to determine the tissues through which the ultrasound
passes on its way to the target can be used for the targeting and safety. From a safety
perspective, such data is important so that the ultrasound does not hit bone or bowel
and that the transducer is properly placed to target the region around the renal blood
vessels. Also included in the system is a cooling system to transfer heat from the
transducer to fluid 9662 running through the system. Cooling via this mechanism allows
for cooling of the ultrasound transducer as well as the skin beneath the system. A
further feature of the system is a sensor mechanism 9665 which is coupled to the system
9650 and records movement of the system 9650 relative to a baseline or a coordinate
nearby. In one embodiment, a magnetic sensor is utilized in which the sensor can determine
the orientation of the system relative to a magnetic sensor on the system. The sensor
9665 is rigidly coupled to the movement mechanism 9660 and the imaging transducer
9675. In addition to magnetic, the sensor might be optoelectric, acoustic, or radiofrequency
based.
[0325] Furthermore, the face 9672 of the transducer 9670 is shaped such that is fits within
the bony region described and depicted in figure 26A. For example, the shape might
be elliptical or aspheric ro in some cases shperic. In addition, in some embodiments
the ultrasound imaging engine might not be directly in the center of the device and
in fact might be superior to the center and closer to the superior border of the face
and closer to the ribs, wherein the renal artery is visualized better with the imaging
probe 9675.
[0326] Given the clinical data as well as the devised technologies described above (e.g.
Figure 26A-B), figure 27 illustrates the novel treatment plan 9700 to apply energy
to the nerves around the renal artery with energy delivered from a position external
to the patient.
[0327] In one embodiment, the patient is stabilized and/or positioned such that the renal
artery and kidneys are optimally located 9710. Diagnostic ultrasound 9730 is applied
to the region and optionally, ultrasound is applied from a second direction 9715.
The positioning and imaging maneuvers allow the establishment of the location of the
renal artery, the hilum, and the vein 9720. A test dose of therapeutic energy 9740
can be applied to the renal hilum region. In some embodiments, temperature 9735 can
be measured. This test dose can be considered a full dose if the treatment is in fact
effective by one or more measures. These measures might be blood pressure 9770, decrease
in sympathetic outflow (as measured by microneurography 9765), increase in parasympathetic
outflow, change in the caliber of the blood vessel 9755 or a decrease in the number
of spontaneous spikes in a microneurographic analysis in a peripheral nerve (e.g.
peroneal nerve) 9765, or an MRI or CT scan which reveals a change in the nervous anatomy
9760. In some embodiments, indices within the kidney are utilized for feedback. For
example, the resistive index,, a measure of the vasoconstriction in the kidney measured
by doppler ultrasound is a useful index related to the renal nerve activity; for example,
when there is greater autonomic activity, the resistive index increases, and vice
versa.
[0328] Completion of the treatment 9745 might occur when the blood pressure reaches a target
value 9770. In fact, this might never occur or it may occur only after several years
and treatment. The blood pressure might continually be too high and multiple treatments
may be applied over a period of years...the concept of dose fractionation. Fractionation
is a major advantage of applying energy from a region external to a region around
the renal arteries in the patient as it is more convenient and less expensive when
compared to invasive treatments such stimulator implantation and interventional procedures
such as catheterization of the renal artery.
[0329] Another important component is the establishment of the location and position of
the renal artery, renal vein, and hilum of the kidney 9720. As discussed above, the
utilization of Doppler ultrasound signaling allows for the position of the nerves
to be well approximated such that the ultrasound can be applied to the general region
of the nerves. The region of the nerves can be seen in Figures 29A-D. Figs 29A-C are
sketches from actual histologic slices. The distances from the arterial wall can be
seen at different locations and generally range from 0.3 mm to 10 mm. Nonetheless,
these images are from actual renal arteries and nerves and are used so as to develop
the treatment plan for the system. For example, once the arterial wall is localized
9730 using the Doppler or other ultrasound signal, a model of the position of the
nerves can be established and the energy then targeted to that region to inhibit the
activity of the nerves 9720. Notably, the distance of many of these nerves from the
wall of the blood vessel indicate that a therapy which applies radiofrequency to the
wall of the vessel from the inside of the vessel likely has great difficulty in reaching
a majority of the nerves around the blood vessel wall.
[0330] Figure 29D depicts a schematic from a live human ultrasound. As can be seen, the
ultrasound travels through skin, through the subcutaneous fat, through the muscle
and at least partially through the kidney 8935 to reach the hilum 8941 of the kidney
and the renal blood vessels 8937. This direction was optimized through clinical experimentation
so as to not include structures which tend to scatter ultrasound such as bone and
lung. Experimentation lead to the optimization of this position for the imaging and
therapy of the renal nerves. The position of the ultrasound is between the palpable
bony landmarks on the posterior of the patient as described above and below. The vertebrae
are medial, the ribs superior and the iliac crest inferior. Importantly, the distance
of these structures 8943 is approximately 8-12 cm and not prohibitive from a technical
standpoint. These images from the ultrasound are therefore consistent with the results
from the CT scans descrbied above as well.
[0331] Figure 29E depicts the surface area 8760 available to an ultrasound transducer for
two patients out of a clinical study. One patient was obese and the other thinner.
Quantification of this surface area 8762 was obtained by the following methodology:
1) obtain CT scan; 2) mark off boundary of organs such as the vertebrae, iliac crest,
and ribs; 3) draw line from renal blood vessels to the point along the edge of the
bone; 4) draw perpendicular from edge bone to the surface of the skin; 5) map the
collection of points obtained along the border of the bone. The surface area is the
surface area between the points and the maximum diameter is the greatest distance
between the bony borders. The collection of points obtained with this method delimits
the area on the posterior of the patient which is available to the ultrasound transducer
to either visualize or treat the region of the focal spot. By studying a series of
patients, the range of surface areas was determined so as to assist in the design
which will serve the majority of patients. The transducers modeled in Figure 30 have
surface areas of approximately 11 x8 cm or 88 cm
2 which is well within the surface area shown in figure 29E 8762 which is representative
of a patient series. Further more the length, or distance, from the renal artery to
the skin was quantified in shortest ray 8764 and longest ray 8766. Along with the
the angular data presented above, these data enable design of an appropriate transducer
to achieve autonomic modulation and control of blood pressure.
[0332] In a separate study, it was shown that these nerves could be inhibited using ultrasound
applied externally with the parameters and devices described herein. Pathologic analysis
revealed that the nerves around the artery were completely inhibited and degenerated,
confirming the ability of the treatment plan to inhibit these nerves and ultimately
to treat diseases such as hypertension. Furthermore, utilizing these parameters, did
not cause any damage within the path of the ultrasound through the kidney and to the
renal hilum.
[0333] Importantly, it has also been discovered via clinical trials that when ultrasound
is used as the energy applied externally, that centering the diagnostic ultrasound
probe such that a cross section of the kidney is visualized and the vessels are visualized,
is an important component of delivering the therapy to the correct position along
the blood vessels. One of the first steps in the algorithm 9700 is to stabilize the
patient in a patient stabilizer custom built to deliver energy to the region of the
renal arteries. After stabilization of the patient, diagnostic ultrasound is applied
to the region 9730 to establish the extent of the ribs, vertebrae, and pelvis location.
Palpation of the bony landmarks also allows for the demarcation of the treatment zone
of interest. The external ultrasound system is then placed within these regions so
as to avoid bone. Then, by ensuring that a portion of the external energy is delivered
across the kidney (for example, using ultrasound for visualization), the possibility
of hitting bowel is all but eliminated. The ultrasound image in Figure 29D depicts
a soft tissue path from outside the patient to the renal hilum inside the patient.
The distance is approximately 8-16 cm. Once the patient is positioned, a cushion 9815
is placed under the patient. In one embodiment, the cushion 9815 is simply a way to
prop up the back of the patient. In another embodiment, the cushion 9815 is an expandable
device in which expansion of the device is adjustable for the individual patient.
The expandable component 9815 allows for compression of the retroperitoneum (where
the kidney resides) to slow down or dampen movement of the kidney and maintain its
position for treatment with the energy source or ultrasound.
[0334] A test dose of energy 9740 can be given to the region of the kidney hilum or renal
artery and temperature imaging 9735, constriction of blood vessels 9755, CT scans
9760, microneurography 9765 patch or electrode, and even blood pressure 9770. Thereafter,
the treatment can be completed 9745. Completion might occur minutes, hours, days,
or years later depending on the parameter being measured.
[0335] Through experimentation, it has been determined that the region of the renal hilum
and kidneys can be stabilized utilizing gravity with local application of force to
the region of the abdomen below the ribs and above the renal pelvis. For example,
Figures 28A-C depict examples of patient positioners intended to treat the region
of the renal blood vessels.
[0336] Figure 28A is one example of a patient positioned in which the ultrasound diagnostic
and therapeutic 9820 is placed underneath the patient. The positioner 9810 is in the
form of a tiltable bed. A patient elevator 9815 placed under the patient pushes the
renal hilum closer to the skin and can be pushed forward in this manner; as determined
in clinical trials, the renal artery is approximately 2-3 cm more superficial in this
type of arrangement with a range of approximately 7-15cm in the patients studied within
the clinical trial. The weight of the patient allows for some stabilization of the
respiratory motion which would otherwise occur; the patient elevator can be localized
to one side or another depending on the region to be treated.
[0337] Figure 28B detects a more detailed configuration of the ultrasound imaging and therapy
engine 9820 inset. A patient interface 9815 is utilized to create a smooth transition
for the ultrasound waves to travel through the skin and to the kidneys for treatment.
The interface is adjustable such that it is customizable for each patient.
[0338] Figure 28C depicts another embodiment of a positioner device 9850, this time meant
for the patient to be face down. In this embodiment, the patient is positioned in
the prone position lying over the patient elevator 9815. Again, through clinical experimentation,
it was determined that the prone position with the positioner under the patient pushes
the renal hilum posterior and stretches out the renal artery and vein allowing them
to be more visible to ultrasound and accessible to energy deposition in the region.
The positioner underneath the patient might be an expandable bladder with one or more
compartments which allows for adjustability in the amount of pressure applied to the
underside of the patient. The positioner might also have a back side which is expandable
9825 and can push against the posterior side of the patient toward the expandable
front side of the positioner thereby compressing the stretched out renal blood vessels
to allow for a more superficial and easier application of the energy device. These
data can be seen in Figs 7G and 7H where the renal artery is quite a bit closer to
the skin (7-17cm down to 6-10cm). The position of the energy devices for the left
side 9827 of the patient and right side 9828 of the patient are depicted in Figure
28C. The ribs 9829 delimit the upper region of the device placement and the iliac
crest 9831 delimits the lower region of the device placement. The spinous processes
9832 delimit the medial edge of the region where the device can be placed and the
region between 9828 is the location where the therapeutic transducer is placed.
[0339] The table elevation is on the front side of the patient, pushing upward toward the
renal hilum and kidneys. The head of the table may be dropped or elevated so as to
allow specific positioning positions. The elevated portion may contain an inflateable
structure which controllably applies pressure to one side or another of the torso,
head, or pelvis of the patient.
[0340] Figure 29A-C depicts the anatomical basis 9900 of the targeting approach described
herein. These figures are derived directly from histologic slides. Nerves 9910 can
be seen in a position around renal artery 9920. The range of radial distance from
the artery is out to 2 mm and even out to 10 mm. Anatomic correlation with the modeling
in Figure 16B reveals the feasibility of the targeting and validates the approach
based on actual pathology; that is, the approach of applying therapy to the renal
nerves by targeting the adventitia of the artery. This is important because the methodology
used to target the nerves is one of detecting the Doppler signal from the artery and
then targeting the vessel wall around the doppler signal. Nerves 9910 can be seen
surrounding the renal artery 9920 which puts them squarely into the temperature field
shown in 16B indicating the feasibility of the outlined targeting approach in Figure
27 and the lesion configuration in Figure 16A. Further experimentation (utilizing
similar types of pathology as well as levels of norepinephrine in the kidney) reveals
that the required dose of ultrasound to the region to affect changes in the nerves
is on the order of 100 W/cm
2 for partial inhibition of the nerves and 1-2 kW/cm
2 for complete inhibition and necrosis of the nerves. These doses or doses in between
them might be chosen depending on the degree of nerve inhibition desired in the treatment
plan. Importantly, it was further discovered through the experimentation that an acoustic
plane through the blood vessels was adequate to partially or completely inhibit the
nerves in the region. That is to say, that a plane through which the blood vessels
travels perpendicularly is adequate to ablate the nerves around the artery as illustrated
in Figure 16B. Until this experimentation, there had been no evidence that ultrasound
would be able to inhibit nerves surrounding an artery by applying a plane of ultrasound
through the blood vessel. Indeed, it was proven that a plane of ultrasound essentially
could circumferentially inhibit the nerves around the blood vessel.
[0341] Figures 30A-I depict three dimensional simulations from a set of CT scans from the
patient model shown in figure 26A. Numerical simulations were performed in three dimensions
with actual human anatomy from the CT scans. The same CT scans utilized to produce
figures 7E, 19, and 25 were utilized to simulate a theoretical treatment of the renal
artery region considering the anatomy of a real patient. Utilizing the doses shown
in the experimentation above (Figs 29A-D) combined with the human anatomy from the
CT scans, it is shown with these simulations that the ability exists to apply therapeutic
ultrasound to the renal hilum from a position outside the patient. In combination
with figure 29, which as discussed, depicts the position of the nerves around the
blood vessels as well as the position of the vessels in an ultrasound, figure 30A-I
depicts the feasibility of an ultrasound transducer which is configured to apply the
required energy to the region of the hilum of the kidney without damaging intervening
structures. These simulations are in fact confirmation for the proof of concept for
this therapy and incorporate the knowledge obtained from the pathology, human CT scans,
human ultrasound scans, and the system designs presented previously above.
[0342] In one embodiment, Figure 30A, the maximum intensity is reached at the focus 10010
is approximately 186 W/cm
2 with a transducer 10000 design at 750 MHz; the transducer is approximately 11 x 8
cm with a central portion 10050 for an ultrasound imaging engine. The input wattage
to the transducer is approximately 120W-150W depending on the specific patient anatomy.
[0343] Figures 30B and 30C depict the acoustic focus 10020, 10030 at a depth of approximately
9-11 cm and in two dimensions. Importantly, the region (tissues such as kidney, ureter,
skin, muscle) proximal (10040 and 10041) to the focus 10020, 10030 do not have any
significant acoustic power absorption indicating that the treatment can be applied
safely to the renal artery region through these tissues as described above. Importantly,
the intervening tissues are not injured in this simulation indicating the feasibility
of this treatment paradigm.
[0344] Figures 30D-F depict a simulation with a transducer 10055 having a frequency of approximately
1 MHz. With this frequency, the focal spot 10070, 10040, 10050 size is a bit smaller
(approximately 2 cm by 0.5 cm) and the maximum power higher at the focus, approximately
400 W/cm
2 than shown in Figures 30A-C. In the human simulation, this is close to an optimal
response and dictates the design parameters for the externally placed devices. The
transducer in this design is a rectangular type of design (spherical with the edges
shaved off) so as to optimize the working space in between the posterior ribs of the
patient and the superior portion of the iliac crest of the patient. Its size is approximately
11 cm x 8 cm which as described above and below is well within the space between the
bony landmarks of the back of the patient.
[0345] Figures 30G-I depict a simulation with similar ultrasound variables as seen in Figs
30D-F. The difference is that the transducer 10090 was left as spherical with a central
cutout rather than rectangular with a central cutout. The spherical transducer setup
10090 allows for a greater concentration of energy at the focus 1075 due to the increased
surface area of vibratory energy. Indeed, the maximum energy from this transducer
(Fig 30G) is approximately 744 W/cm
2 whereas for the transducer in figure 30d, the maximum intensity is approximately
370 W/cm
2. Figure 30H depicts one plane of the model and 30I another plane. Focus 10080,10085
is depicted with intervening regions 10082 and 10083 free from acoustic power and
heat generation, similar to Figure 30A-F.
[0346] These simulations confirm the feasibility of a therapeutic treatment of the renal
sympathetic nerves from the outside without damage to intervening tissues or structures
such as bone, bowel, and lung. Hypertension is one clinical application of this therapy.
A transducer with an imaging unit within is utilized to apply focused ultrasound to
a renal nerve surrounding a renal artery. Both the afferent nerves and efferent nerves
are affected by this therapy.
[0347] Other transducer configurations are possible. Although a single therapeutic transducer
is shown in Figure 30A-I, configurations such as phased array therapy transducers
(more than one independently controlled therapeutic transducer) are possible. Such
transducers allow more specific tailoring to the individual patient. For example,
a larger transducer might be utilized with 2,3,4 or greater than 4 transducers. Individual
transducers might be turned on or off depending on the patients anatomy. For example,
a transducer which would cover a rib in an individual patient might be turned off
during the therapy.
[0348] Although the central space is shown in the center of the transducer in figures 30A-I,
the imaging transducer might be placed anywhere within the field as long as its position
is well known relative to the therapy transducers. For example, insofar as the transducer
for therapy is coupled to the imaging transducer spatially in three dimensional space
and this relationship is always known, the imaging transducer can be in any orientation
relative to the therapeutic transducer.
[0349] The present application is a divisional application of parent application
EP 10 823 909.6. The following numbered clauses were claims of the parent application and are subject-matter
of, but not claims of, the present application.
1. A method of treatment, comprising:
placing an energy source outside a patient;
operating the energy source so that an energy delivery path of the energy source is
aimed towards a nerve inside the patient, wherein the nerve is a part of an autonomic
nervous system; and
using the energy source to deliver treatment energy from outside the patient to the
nerve located inside the patient to treat the nerve.
2. The method of clause 1, wherein the treatment energy comprises focused energy.
3. The method of clause 1, wherein the treatment energy comprises non-focused energy.
4. The method of clause 1, wherein the treatment energy comprises HIFU energy.
5. The method of clause 1, wherein the treatment energy comprises LIFU energy.
6. The method of clause 1, wherein the treatment energy is delivered to the nerve
to achieve partial ablation of the nerve.
7. The method of clause 1, wherein the treatment energy is delivered to the nerve
to achieve complete ablation of the nerve.
8. The method of clause 1, wherein the treatment energy is delivered to achieve paralysis
of the nerve.
9. The method of clause 1, wherein the nerve leads to a kidney.
10. The method of clause 9, wherein the nerve comprises a renal nerve.
11. The method of clause 9, wherein the nerve comprises a sympathetic nerve connected
to the kidney.
12. The method of clause 9, wherein the nerve comprises an afferent nerve connected
to the kidney.
13. The method of clause 9, wherein the nerve comprises a renal sympathetic nerve
at a renal pedicle.
14. The method of clause 1, wherein the nerve comprises a nerve trunk adjacent to
a vertebra.
15. The method of clause 1, wherein the nerve comprises a ganglion adjacent to a vertebra.
16. The method of clause 1, wherein the nerve comprises a dorsal root nerve.
17. The method of clause 1, wherein the nerve leads to an adrenal gland.
18. The method of clause 1, wherein the nerve comprises a motor nerve.
19. The method of clause 1, wherein the nerve is next to a kidney.
20. The method of clause 1, wherein the nerve is behind an eye.
21. The method of clause 1, wherein the nerve comprises a celiac plexus.
22. The method of clause 1, wherein the nerve is within or around a vertebral column.
23. The method of clause 1, wherein the nerve extends to a facet joint
24. The method of clause 1, wherein the nerve comprises a celiac ganglion.
25. The method of clause 1, wherein the act of operating the energy source comprises
positioning the energy source.
26. The method of clause 1, wherein the energy source comprises an ultrasound energy
source.
27. The method of clause 26, wherein the ultrasound energy source is used to deliver
the treatment energy to the nerve from multiple directions outside the patient.
28. The method of clause 1, wherein the treatment energy is delivered to modulate
the nerve without damaging the nerve.
29. The method of clause 1, further comprising determining a position of a renal vessel
using an imaging device located outside the patient.
30. The method of clause 29, wherein the position of the renal vessel is used to determine
a position of the nerve.
31. The method of clause 29, wherein the imaging device comprises a CT device, an
MRI device, a thermography device, an infrared imaging device, an optical coherence
tomography device, a photoacoustic imaging device, a PET imaging device, a SPECT imaging
device, or an ultrasound device.
32. The method of clause 1, further comprising determining a position of the nerve
inside the patient.
33. The method of clause 32, wherein the act of determining the position of the nerve
inside the patient comprises determining a position of a renal vessel to target the
nerve that surrounds the renal vessel.
34. The method of clause 33, wherein the renal vessel comprises a renal artery.
35. The method of clause 32, wherein the act of determining the position of the nerve
inside the patient comprises using a Doppler triangulation technique.
38. The method of clause 32, wherein the imaging device comprises a MRI device.
39. The method of clause 32, wherein the imaging device comprises a CT device.
40. The method of clause 32, wherein the treatment energy comprises HIFU energy, and
the imaging device comprises a MRI device.
41. The method of clause 32, wherein the treatment energy comprises HIFU energy, and
the imaging device comprises an ultrasound device.
42. The method of clause 32, wherein the nerve leads to a kidney, and the imaging
device comprises a MRI device.
43. The method of clause 32, wherein the nerve leads to a kidney, and the imaging
device comprises an ultrasound device.
44. The method of clause 32, wherein the nerve leads to a kidney, and the imaging
device is used to obtain a doppler signal.
45. The method of clause 1, wherein the treatment energy is delivered to a kidney
to decrease a sympathetic stimulus to the kidney, decrease an afferent signal from
the kidney to an autonomic nervous system, or both.
46. The method of clause 1, further comprising delivering testing energy to the patient
to determine if there is a reaction resulted therefrom, wherein the testing energy
is delivered before the treatment energy is delivered from the energy source.
47. The method of clause 46, wherein the testing energy comprises heat or vibratory
energy, and the method further comprises performing a test to detect sympathetic nerve
activity.
48. The method of clause 46, wherein the testing energy comprises a stimulus applied
to a skin, and the method further comprises detecting an output from the patient.
49. The method of clause 48, wherein the output comprises a heart rate.
50. The method of clause 46, wherein the test energy is delivered to stimulate a baroreceptor
complex, and wherein the method further comprises:
applying pressure to a carotid artery; and
determining whether a blood pressure decreases after application of the pressure to
the carotid artery.
51. The method of clause 50, wherein the test energy is delivered using an ultrasound
device that is placed outside the patient.
52. The method of clause 50, wherein the treatment energy from the energy source is
delivered if the blood pressure decreases or if the blood pressure decreases at a
rate that is above a prescribed threshold.
53. The method of clause 1, wherein the treatment energy is delivered to treat hypertension.
54. The method of clause 1, wherein the treatment energy is delivered to treat glaucoma.
55. The method of clause 1, wherein the energy source is operated so that the energy
source aims at a direction that aligns with a vessel that is next to the nerve.
56. The method of clause 1, further comprising tracking a movement of a treatment
region containing the nerve.
57. The method of clause 1, wherein the energy delivery path of the energy source
is aimed towards the nerve by using a position of a blood vessel that is surrounded
by the nerve.
58. The method of clause 1, further comprising:
delivering a device inside the patient; and
using the device to determine a position of the nerve inside the patient;
wherein the energy source is operated based at least in part on the determined position
so that the energy delivery path is aimed towards the nerve.
59. The method of clause 58, wherein the device is placed inside a vessel that is
surrounded by the nerve, and the position of the nerve is determined indirectly by
determining a position of the vessel.
60. A system for treatment, comprising:
an energy source for placement outside a patient;
wherein the energy source is configured to aim an energy delivery path towards a nerve
that is a part of an autonomic nervous system inside the patient; and
wherein the energy source is configured to deliver treatment energy from outside the
patient to the nerve located inside the patient to treat the nerve.
61. The system of clause 60, wherein the energy source is configured to provide focused
energy.
62. The system of clause 60, wherein the energy source is configured to provide non-focused
energy.
63. The system of clause 60, wherein the energy source is configured to provide HIFU
energy.
64. The system of clause 60, wherein the energy source is configured to provide LIFU
energy.
65. The system of clause 60, wherein the energy source is configured to provide the
treatment energy to achieve partial ablation of the nerve.
66. The system of clause 60, wherein the energy source is configured to deliver the
treatment energy to achieve complete ablation of the nerve.
67. The system of clause 60, wherein the energy source is configured to deliver the
treatment energy to achieve paralysis of the nerve.
68. The system of clause 60, wherein the energy source comprises an ultrasound energy
source.
69. The system of clause 68, wherein the ultrasound energy source is configured to
deliver the treatment energy to the nerve from multiple directions outside the patient
while the ultrasound energy source is stationary relative to the patient.
70. The system of clause 60, wherein the energy source is configured to deliver the
treatment energy to modulate the nerve without damaging tissues that are within a
path of the treatment energy to the nerve.
71. The system of clause 60, wherein the nerve comprises a renal nerve, and the system
further comprises a processor located outside the patient, wherein the processor is
configured for:
receiving an input related to a position of a renal artery;
determining an output related to a position of the renal nerve based on a model that
associates artery position with nerve position; and
providing the output to a positioning system for the energy source so that the positioning
system can cause the energy source to deliver the treatment energy from the outside
of the patient to the renal nerve to treat the renal nerve.
72. The system of clause 60, further comprising a processor for determining a position
of a renal vessel located outside the patient.
73. The system of clause 72, further comprising an imaging device for providing an
image signal, wherein the processor is configured to determine the position based
on the image signal.
74. The system of clause 73, wherein the imaging device comprises a CT device, a MRI
device, a thermography device, an infrared imaging device, an optical coherence tomography
device, a photoacoustic imaging device, a PET imaging device, a SPECT imaging device,
or an ultrasound device.
75. The system of clause 72, wherein the position of the renal vessel is used during
the treatment energy delivery to target the nerve that surrounds the renal vessel.
76. The system of clause 72, wherein the position is determined using a Doppler triangulation
technique.
77. The system of clause 72, wherein the renal vessel comprises a renal artery.
78. The system of clause 60, wherein treatment energy is delivered to a kidney to
decrease a sympathetic stimulus to the kidney, decrease an afferent signal from the
kidney to an autonomic nervous system, or both.
79. The system of clause 60, wherein the energy source is also configured to deliver
testing energy to the patient to determine if there is a reaction resulted therefrom.
80. The system of clause 60, wherein the energy source is configured to deliver the
treatment energy to treat hypertension.
81. The system of clause 60, wherein the energy source is configured to deliver the
treatment energy to treat glaucoma.
82. The system of clause 60, wherein the energy source has an orientation so that
the energy source aims at a direction that aligns with a vessel that is next to the
nerve.
83. The system of clause 60, wherein the energy source is configured to track a movement
of the nerve.
84. The system of clause 83, wherein the energy source is configured to track the
movement of the nerve by tracking a movement of a blood vessel next to the nerve.
85. The system of clause 60, wherein the energy source is configured to aim at the
nerve by aiming at a vessel that is surrounded by the nerve.
86. The system of clause 60, further comprising:
a device for placement inside the patient; and
a processor for determining a position using the device;
wherein the energy source is configured to aim the energy delivery path towards the
nerve inside the patient based at least in part on the determined position.
87. The system of clause 86, wherein the device is sized for insertion into a vessel
that is surrounded by the nerve.
88. A system to deliver energy from a position outside a skin of a patient to a nerve
surrounding a blood vessel inside the patient, comprising:
a processor configured to receive image signal, and determine a three dimensional
coordinate of a blood vessel based on the image signal; and
an energy source configured to deliver energy from the position outside the skin of
the patient to the nerve surrounding the blood vessel;
wherein the processor is also configured to control the energy source based on the
determined coordinate.
89. The system of clause 88, further comprising an imaging device for providing the
image signal.
90. The system of clause 89, wherein the imaging device comprises a MRI device.
91. The system of clause 89, wherein the imaging device comprises an ultrasound device.
92. The system of clause 88, wherein the energy comprises focused energy.
93. The system of clause 88, wherein the energy comprises focused ultrasound.
94. The system of clause 88, wherein the energy source comprises an ultrasound array
that is aligned with the vessel.
95. The system of clause 88, further comprising an imaging device for providing a
B-mode ultrasound for imaging the blood vessel.
96. A system to deliver energy from a position outside a skin of a patient to a nerve
surrounding a blood vessel comprising:
a fiducial for placement inside the blood vessel;
a detection device to detect the fiducial inside the blood vessel;
a processor configured to determine a three dimensional coordinate of the detected
fiducial; and
an energy source configured to transmit energy through the skin and to focus the energy
at the region of the blood vessel;
wherein the processor is configured to operate the energy source based on the determined
three dimensional coordinate of the fiducial, and information regarding the blood
vessel.
97. The system of clause 96, wherein the energy source comprises an ultrasound device,
and wherein the blood vessel is a renal artery.
98. The system of clause 96, further comprising an ultrasound imaging system.
99. The system of clause 96, wherein the fiducial is placed inside the blood vessel
and is attached to an intravascular catheter.
100. The system of clause 96, wherein the fiducial is a passive fidicial that is configured
to respond to an external signal.
101. The system of clause 96, wherein the fiducial is an active ficucial, transmitting
its position to the detection device.
102. A method to treat hypertension in a patient comprising:
obtaining an imaging signal from a blood vessel in the patient;
planning a delivery of energy to a wall of the blood vessel; and
delivering energy from outside a skin of the patient to an autonomic nerve surrounding
the blood vessel.
103. The method of clause 102, further comprising selectively modulating an afferent
nerve within a sympathetic nerve bundle.
104. The method of clause 102, further comprising utilizing microneurography after
the delivery of the energy to determine an effect of the energy delivery on a sympathetic
nervous system.
105. The method of clause 102, wherein the blood vessel extends to or from a kidney,
and the method further comprises locating the blood vessel with doppler ultrasound.
106. A system to modulate an autonomic nerve in a patient utilizing transcutaneous
energy delivery, the system comprising:
a processor comprising;
an input for receiving information regarding energy and power to be delivered to a
treatment region containing the nerve; and
an output for outputting a signal;
wherein the processor is configured to determine a position of a reference target
from outside the patient to localize the nerve relative to the reference target;
a therapeutic energy device comprising:
a transducer for delivering energy from outside the patient;
a controller to control an aiming of the transducer based at least in part on the
signal from the
processor; and
an imaging system coupled to the processor or the therapeutic energy device.
107. The system of clause 106, wherein the processor is configured to determine the
position during an operation of the therapeutic energy device.
108. The system of clause 106, further comprising a patient interface configured to
position the therapeutic device so that the transducer is aimed toward a blood vessel
connected to a kidney from a position between ribs superiorly, a iliac crest inferiorly,
and a vertebral column medially.
109. The system of clause 106, wherein the therapeutic energy device is configured
to deliver focused ultrasound.
110. The system of clause 106, wherein the reference target is at least a portion
of a blood vessel traveling to or from a kidney, and the nerve is a renal nerve.
111. The system of clause 110, wherein the transducer is configured to focus energy
at a distance from 6 cm to 18 cm.
112. The system of clause 106, wherein the transducer is configured to deliver the
energy in a form of focused ultrasound to a renal blood vessel at an angle ranging
between about -10 degrees and about -48 degrees relative to a horizontal line connecting
transverse processes of a spinal column.
113. The system of clause 106, wherein the energy from the therapeutic energy device
ranges between 100 W/cm2 and 2500 W/cm2.
114. The system of clause 106, wherein the reference target is an indwelling vascular
catheter.
115. The system of clause 106, wherein the imaging system is a magnetic resonance
imaging system and the therapeutic energy device is an ultrasound device.
116. The system of clause 106, wherein the imaging system is an ultrasound imaging
system.
117. The system of clause 106, wherein the processor is a part of the therapeutic
energy device.
118. The system of clause 106, wherein the processor is a part of the imaging system.
119. A method to deliver energy from a position outside the skin of a patient to a
nerve surrounding a blood vessel, comprising:
placing a device inferior to ribs, superior to an iliac crest, and lateral to a spine;
using the device to maintain an energy delivery system at a desired position relative
to the patient so that the energy delivery system can deliver energy through the skin
without traversing bone.
120. The method of clause 119, wherein the energy delivery system comprises a focused
ultrasound delivery system.
121. A device for use in a system to deliver focused ultrasound energy from a position
outside a skin of a patient to a nerve surrounding a blood vessel, comprising:
a positioning device configured to maintain an energy delivery system at a desired
position relative to the patient so that the energy delivery system can deliver energy
through the skin without traversing bone;
wherein the positioning device is configured to be placed inferior to ribs, superior
to an iliac crest, and lateral to a spine.
122. The device of clause 121, wherein the energy delivery system comprises a focused
ultrasound delivery system.
123. The device of clause 122, wherein the positioning device is configured to maintain
an angle of the focused ultrasound delivery system such that bony structures are not
include in an ultrasound field.
124. A system for treatment, comprising:
a treatment device configured to deliver energy from outside a patient to a nerve
inside the patient;
a catheter configured for placement inside a vessel surrounded by the nerve, the catheter
configured to transmit a signal; and
a processor configured to receive the signal and determine a reference position in
the vessel;
wherein the treatment device is configured deliver the energy to the nerve based on
the determined reference position.
125. The system of clause 124, wherein the treatment device comprises an ultrasound
device.
126. A method of inhibiting the function of a nerve traveling with an artery comprising:
providing an external imaging modality to determine the location of the artery of
a patient;
placing the artery in a first three dimensional coordinate reference based on the
imaging;
placing or associating a therapeutic energy generation source in the first three dimensional
coordinate reference frame;
modeling the delivery of energy to the adventitial region of the artery or a region
adjacent to the artery where a nerve travels;
delivering therapeutic energy from the therapeutic energy source, from at least two
different angles, through the skin of a patient, to intersect at the artery or the
region adjacent to the artery;
and, at least partially inhibiting the function of the nerve traveling with the artery.
127. The method of clause 126, wherein the imaging modality is one of: ultrasound,
MRI, and CT.
128. The method of clause 126, wherein the therapeutic energy is ultrasound.
129. The method of clause 126, wherein the artery is a renal artery.
130. The method of clause 126, wherein placing the artery in a three dimensional reference
frame comprises locating the artery using a doppler ultrasound signal.
131. The method of clause 126, further comprising: utilizing a fiducial wherein the
fiducial is placed internal to the patient.
132. The method of clause 131, wherein said fiducial is temporarily placed in a position
internal to the patient.
133. The method of clause 131, wherein said fiducial is a catheter placed in the artery
of the patient.
134. The method of clause 133, wherein said catheter is detectable using a radiofrequency
signal and said imaging modality is ultrasound.
135. The method of clause 126, wherein the therapeutic energy from the energy source
is delivered in a distribution along the length of the artery.
136. The method of clause 126, wherein the therapeutic energy is ionizing radiation.
137. A system to inhibit the function of a nerve traveling with a renal artery comprising:
a detector to determine the location of the renal artery and renal nerve from a position
external to a patient;
an ultrasound component to deliver therapeutic energy through the skin from at least
two directions to the nerve surrounding the renal artery;
a modeling algorithm comprising an input and an output, said input to the modeling
algorithm comprising a three dimensional coordinate space containing a therapeutic
energy source and the position of the renal artery in the three dimensional coordinate
space; and,
said output from the modeling algorithm comprising: the direction and energy level
of the ultrasound component;
a fiducial, locatable from a position outside a patient, adapted to be temporarily
placed in the artery of the patient and communicate with the detector to determine
the location of the renal artery in a three dimensional reference frame, the information
regarding the location transmittable as the input to the model.
138. The system of clause 137, wherein the fiducial is a passive reflector of ultrasound.
139. The system of clause 137, wherein the fiducial generates radiofrequency energy.
140. The system of clause 137, wherein the fiducial is activated to transmit energy
based on a signal from an ultrasound or magnetic field generator.
141. The system of clause 137, wherein the output from the model instructs the ultrasound
component to deliver a lesion on the artery in which the major axis of the lesion
is longitudinal along the length of the artery.
142. The system of clause 141, wherein the output from the model instructs the ultrasound
component to deliver multiple lesions around an artery simultaneously.
143. The system of clause 137, wherein the output from the model instructs the ultrasound
component to deliver a circumferential lesion around the artery.
144. The system of clause 141, wherein the lesion is placed around the renal artery
just proximal to the bifurcation of the artery in the hilum of the kidney.
145. A method to stimulate or inhibit the function of a nerve traveling to or from
the kidney comprising:
- a. Identifying an acoustic window at the posterior region of a patient in which the
renal arteries can be visualized;
- b. transmitting a first energy through the skin of a patient from the posterior region
of the patient;
- c. imaging an arterial region using the first transmitted energy;
- d. applying a second transmitted energy to the arterial adventitia by coupling the
imaging and the second transmitted energy.
146. The method of clause 145, further comprising: tracking the image created by the
first transmitted energy.
147. A method to locate the position of a blood vessel in the body of a patient comprising:
applying a first wave of ultrasound, from a first direction, to a region of a blood
vessel from outside of the patient and detecting its return signal;
comparing the applied first wave and its return signal;
simultaneously, or sequentially, applying a second wave of ultrasound from a second
direction to the blood vessel and detecting a its return signal;
integrating the return signals from the first wave and the return signals from the
second wave to determine the position, in a three dimensional coordinate reference,
of the blood vessel.
148. The method of clause 147, further comprising the step of instructing a therapeutic
ultrasound transducer to apply energy to the position of the blood vessel.